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Hu P, Shan X, Dong H, Yu S, Wang B, Xiong H, Ji Z, Jing W, Cui Y, Li Z, Zhou Y, Wang Z, Wang J, Tang J, Wang T, Xie K, Yu Q. Macrophage-specific PHGDH protects against MAFLD by suppressing TAK1. Cell Rep 2025; 44:115426. [PMID: 40096087 DOI: 10.1016/j.celrep.2025.115426] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/23/2024] [Revised: 01/26/2025] [Accepted: 02/21/2025] [Indexed: 03/19/2025] Open
Abstract
Metabolic dysfunction-associated fatty liver disease (MAFLD) is a progressive disease with only one approved treatment currently available. Hepatic phosphoglycerate dehydrogenase (PHGDH), the rate-limiting enzyme of the serine biosynthesis pathway, regulates MAFLD development. However, the role of macrophage PHGDH in MAFLD progression remains unclear. Here, we demonstrate that the lipotoxicity inducer palmitic acid (PA) significantly increases macrophage PHGDH expression and that PHGDH deficiency in macrophages promotes PA-induced inflammatory responses. Myeloid-specific PHGDH deficiency exacerbates MAFLD in mice. Mechanistically, tetrameric PHGDH binds to transforming growth factor-β-activated kinase 1 (TAK1) to inhibit its interaction with TAK1 binding protein 1 (TAB1), sequentially suppressing the activation of TAK1 and downstream NF-κB and MAPK signaling. Inhibition of TAK1 activation slows the development of metabolic dysfunction-associated steatohepatitis (MASH) caused by myeloid PHGDH knockout. Importantly, adeno-associated virus-mediated PHGDH overexpression in liver macrophages alleviates MAFLD in mice. Collectively, these results identify macrophage PHGDH as a promising therapeutic agent for MAFLD.
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Affiliation(s)
- Penghui Hu
- Department of Critical Care Medicine, Tianjin Medical University General Hospital, Tianjin 300052, China; Tianjin Institute of Immunology, State Key Laboratory of Experimental Hematology, Key Laboratory of Immune Microenvironment and Disease (Ministry of Education), Department of Immunology, School of Basic Medical Sciences, Tianjin Medical University, Tianjin 300070, China
| | - Xiao Shan
- Department of Health Management Center and Institute of Health Management, Sichuan Provincial People's Hospital, University of Electronic Science and Technology of China, Chengdu 610000, China
| | - Hongyuan Dong
- Tianjin Institute of Immunology, State Key Laboratory of Experimental Hematology, Key Laboratory of Immune Microenvironment and Disease (Ministry of Education), Department of Immunology, School of Basic Medical Sciences, Tianjin Medical University, Tianjin 300070, China
| | - Sujun Yu
- Tianjin Institute of Immunology, State Key Laboratory of Experimental Hematology, Key Laboratory of Immune Microenvironment and Disease (Ministry of Education), Department of Immunology, School of Basic Medical Sciences, Tianjin Medical University, Tianjin 300070, China
| | - Baochen Wang
- Tianjin Institute of Immunology, State Key Laboratory of Experimental Hematology, Key Laboratory of Immune Microenvironment and Disease (Ministry of Education), Department of Immunology, School of Basic Medical Sciences, Tianjin Medical University, Tianjin 300070, China
| | - Hui Xiong
- Tianjin Institute of Immunology, State Key Laboratory of Experimental Hematology, Key Laboratory of Immune Microenvironment and Disease (Ministry of Education), Department of Immunology, School of Basic Medical Sciences, Tianjin Medical University, Tianjin 300070, China
| | - Zemin Ji
- Tianjin Institute of Immunology, State Key Laboratory of Experimental Hematology, Key Laboratory of Immune Microenvironment and Disease (Ministry of Education), Department of Immunology, School of Basic Medical Sciences, Tianjin Medical University, Tianjin 300070, China
| | - Weijia Jing
- Tianjin Institute of Immunology, State Key Laboratory of Experimental Hematology, Key Laboratory of Immune Microenvironment and Disease (Ministry of Education), Department of Immunology, School of Basic Medical Sciences, Tianjin Medical University, Tianjin 300070, China
| | - Yan Cui
- Tianjin Institute of Immunology, State Key Laboratory of Experimental Hematology, Key Laboratory of Immune Microenvironment and Disease (Ministry of Education), Department of Immunology, School of Basic Medical Sciences, Tianjin Medical University, Tianjin 300070, China
| | - Zihan Li
- Tianjin Institute of Immunology, State Key Laboratory of Experimental Hematology, Key Laboratory of Immune Microenvironment and Disease (Ministry of Education), Department of Immunology, School of Basic Medical Sciences, Tianjin Medical University, Tianjin 300070, China
| | - Yanzhao Zhou
- Department of Hepatobiliary Cancer, Liver Cancer Research Center, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin's Clinical Research Center for Cancer, Tianjin 300060, China; Department of Hepatobiliary and Pancreatic Surgery, The Affiliated Cancer Hospital of Zhengzhou University and Henan Cancer Hospital, Zhengzhou 450008, China
| | - Zhe Wang
- Department of Health Management Center and Institute of Health Management, Sichuan Provincial People's Hospital, University of Electronic Science and Technology of China, Chengdu 610000, China
| | - Jinrong Wang
- Tianjin Institute of Immunology, State Key Laboratory of Experimental Hematology, Key Laboratory of Immune Microenvironment and Disease (Ministry of Education), Department of Immunology, School of Basic Medical Sciences, Tianjin Medical University, Tianjin 300070, China
| | - Jiuzhou Tang
- Tianjin Institute of Immunology, State Key Laboratory of Experimental Hematology, Key Laboratory of Immune Microenvironment and Disease (Ministry of Education), Department of Immunology, School of Basic Medical Sciences, Tianjin Medical University, Tianjin 300070, China
| | - Ting Wang
- The Province and Ministry Co-sponsored Collaborative Innovation Center for Medical Epigenetics, School of Basic Medical Sciences, Department of Pharmacology and Tianjin Key Laboratory of Inflammation Biology, Tianjin Medical University, Tianjin 300070, China
| | - Keliang Xie
- Department of Critical Care Medicine, Tianjin Medical University General Hospital, Tianjin 300052, China; Department of Anesthesiology, Tianjin Institute of Anesthesiology, Tianjin Medical University General Hospital, Tianjin 300052, China.
| | - Qiujing Yu
- Department of Health Management Center and Institute of Health Management, Sichuan Provincial People's Hospital, University of Electronic Science and Technology of China, Chengdu 610000, China; Tianjin Institute of Immunology, State Key Laboratory of Experimental Hematology, Key Laboratory of Immune Microenvironment and Disease (Ministry of Education), Department of Immunology, School of Basic Medical Sciences, Tianjin Medical University, Tianjin 300070, China.
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Fernández-Ramos D, Lopitz-Otsoa F, Lu SC, Mato JM. S-Adenosylmethionine: A Multifaceted Regulator in Cancer Pathogenesis and Therapy. Cancers (Basel) 2025; 17:535. [PMID: 39941901 PMCID: PMC11816870 DOI: 10.3390/cancers17030535] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2024] [Revised: 01/30/2025] [Accepted: 02/03/2025] [Indexed: 02/16/2025] Open
Abstract
S-adenosylmethionine (SAMe) is a key methyl donor that plays a critical role in a variety of cellular processes, such as DNA, RNA and protein methylation, essential for maintaining genomic stability, regulating gene expression and maintaining cellular homeostasis. The involvement of SAMe in cancer pathogenesis is multifaceted, as through its multiple cellular functions, it can influence tumor initiation, progression and therapeutic resistance. In addition, the connection of SAMe with polyamine synthesis and oxidative stress management further underscores its importance in cancer biology. Recent studies have highlighted the potential of SAMe as a biomarker for cancer diagnosis and prognosis. Furthermore, the therapeutic implications of SAMe are promising, with evidence suggesting that SAMe supplementation or modulation could improve the efficacy of existing cancer treatments by restoring proper methylation patterns and mitigating oxidative damage and protect against damage induced by chemotherapeutic drugs. Moreover, targeting methionine cycle enzymes to both regulate SAMe availability and SAMe-independent regulatory effects, particularly in methionine-dependent cancers such as colorectal and lung cancer, presents a promising therapeutic approach. Additionally, exploring epitranscriptomic regulations, such as m6A modifications, and their interaction with non-coding RNAs could enhance our understanding of tumor progression and resistance mechanisms. Precision medicine approaches integrating patient subtyping and combination therapies with chemotherapeutics, such as decitabine or doxorubicin, together with SAMe, can enhance chemosensitivity and modulate epigenomics, showing promising results that may improve treatment outcomes. This review comprehensively examines the various roles of SAMe in cancer pathogenesis, its potential as a diagnostic and prognostic marker, and its emerging therapeutic applications. While SAMe modulation holds significant promise, challenges such as bioavailability, patient stratification and context-dependent effects must be addressed before clinical implementation. In addition, better validation of the obtained results into specific cancer animal models would also help to bridge the gap between research and clinical practice.
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Affiliation(s)
- David Fernández-Ramos
- Precision Medicine and Metabolism Lab, Center for Cooperative Research in Biosciences (CIC bioGUNE), Basque Research and Technology Alliance (BRTA), 48160 Derio, Spain; (D.F.-R.); (F.L.-O.)
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Instituto de Salud Carlos III, 28029 Madrid, Spain
| | - Fernando Lopitz-Otsoa
- Precision Medicine and Metabolism Lab, Center for Cooperative Research in Biosciences (CIC bioGUNE), Basque Research and Technology Alliance (BRTA), 48160 Derio, Spain; (D.F.-R.); (F.L.-O.)
| | - Shelly C. Lu
- Karsh Division of Gastroenterology and Hepatology, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA;
| | - José M. Mato
- Precision Medicine and Metabolism Lab, Center for Cooperative Research in Biosciences (CIC bioGUNE), Basque Research and Technology Alliance (BRTA), 48160 Derio, Spain; (D.F.-R.); (F.L.-O.)
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Nielsen MH, Nøhr-Meldgaard J, Møllerhøj MB, Oró D, Pors SE, Andersen MW, Kamzolas I, Petsalaki E, Vacca M, Harder LM, Perfield JW, Veidal S, Hansen HH, Feigh M. Characterization of six clinical drugs and dietary intervention in the nonobese CDAA-HFD mouse model of MASH and progressive fibrosis. Am J Physiol Gastrointest Liver Physiol 2025; 328:G51-G71. [PMID: 39404770 DOI: 10.1152/ajpgi.00110.2024] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/10/2024] [Revised: 09/13/2024] [Accepted: 09/23/2024] [Indexed: 12/17/2024]
Abstract
The choline-deficient l-amino acid defined-high-fat diet (CDAA-HFD) mouse model is widely used in preclinical metabolic dysfunction-associated steatohepatitis (MASH) research. To validate the CDAA-HFD mouse, we evaluated disease progression and responsiveness to dietary and pharmacological interventions with semaglutide, lanifibranor, elafibranor, obeticholic acid (OCA), firsocostat, and resmetirom. Disease phenotyping was performed in C57BL/6J mice fed CDAA-HFD for 3-20 wk and ranked using the MASLD Human Proximity Score (MHPS). Semaglutide, lanifibranor, elafibranor, OCA, firsocostat, or resmetirom were profiled as treatment intervention for 8 wk, starting after 6 wk of CDAA-HFD feeding. Semaglutide and lanifibranor were further evaluated as early (preventive) therapy for 9 wk, starting 3 wk after CDAA-HFD diet feeding. In addition, benefits of dietary intervention (chow reversal) for 8 wk were characterized following 6 wk of CDAA-HFD feeding. CDAA-HFD mice demonstrated a nonobese phenotype with fast onset and progression of MASH and fibrosis, high similarity to human MASH-fibrosis, and tumor development after 20 wk of diet-induction. Semaglutide and lanifibranor partially reversed fibrosis when administered as prevention but not as treatment intervention. Elafibranor was the only interventional drug therapy to improve fibrosis. In comparison, chow-reversal resulted in complete regression of steatosis with improved liver inflammation and fibrosis in CDAA-HFD mice. CDAA-HFD mice recapitulate histological hallmarks of advanced MASH with progressive severe fibrosis, however, in the absence of a clinical translational obese dysmetabolic phenotype. CDAA-HFD mice are suitable for profiling drug candidates directly targeting hepatic lipid metabolism, inflammation, and fibrosis. The timing of pharmacological intervention is critical for determining antifibrotic drug efficacy in the model.NEW & NOTEWORTHY The CDAA-HFD mouse model is widely used in preclinical MASH research, but validation of the model is lacking. This study presents the longitudinal characterization of disease progression. Furthermore, late-stage clinical compounds and dietary intervention (chow reversal) display distinct hepatoprotective effects in the model. Collectively, the study provides critical information guiding the use of the CDAA-HFD mouse model in preclinical drug discovery for MASH and fibrosis.
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Affiliation(s)
| | | | | | | | | | | | - Ioannis Kamzolas
- TVP Lab, WT/MRC Institute of Metabolic Science, University of Cambridge, Cambridge, United Kingdom
- European Molecular Biology Laboratory, European Bioinformatics Institute (EMBL-EBI), Hinxton, United Kingdom
| | - Evangelia Petsalaki
- European Molecular Biology Laboratory, European Bioinformatics Institute (EMBL-EBI), Hinxton, United Kingdom
| | - Michele Vacca
- TVP Lab, WT/MRC Institute of Metabolic Science, University of Cambridge, Cambridge, United Kingdom
- Interdisciplinary Department of Medicine, University of Bari "Aldo Moro", Bari, Italy
- Laboratory of Liver Metabolism and MASLD, Roger Williams Institute of Hepatology, London, United Kingdom
| | - Lea Mørch Harder
- Research and Early Development, Novo Nordisk A/S, Måløv, Denmark
| | - James W Perfield
- Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana, United States
| | - Sanne Veidal
- Research and Early Development, Novo Nordisk A/S, Måløv, Denmark
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Wang Y, Ma H, Zhang B, Li S, Lu B, Qi Y, Liu T, Wang H, Kang X, Liang Y, Kong E, Cao L, Zhou B. Protein palmitoylation in hepatic diseases: Functional insights and therapeutic strategies. J Adv Res 2024:S2090-1232(24)00619-2. [PMID: 39732335 DOI: 10.1016/j.jare.2024.12.041] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/29/2024] [Revised: 12/24/2024] [Accepted: 12/25/2024] [Indexed: 12/30/2024] Open
Abstract
BACKGROUND Liver pathologies represent a spectrum of conditions ranging from fatty liver to the aggressive hepatocellular carcinoma (HCC), as well as parasitic infections, which collectively pose substantial global health challenges. S-palmitoylation (commonly referred to as palmitoylation), a post-translational modification (PTM) characterized by the covalent linkage of a 16-carbon palmitic acid (PA) chain to specific cysteine residues on target proteins, plays a pivotal role in diverse cellular functions and is intimately associated with the liver's physiological and pathological states. AIM OF REVIEW This study aims to elucidate how protein palmitoylation affects liver disease pathophysiology and evaluates its potential as a target for diagnostic and therapeutic interventions. KEY SCIENTIFIC CONCEPTS OF REVIEW Recent studies have identified the key role of protein palmitoylation in regulating the development and progression of liver diseases. This review summarizes the intricate mechanisms by which protein palmitoylation modulates the pathophysiological processes of liver diseases and explores the potential of targeting protein palmitoylation modifications or the enzymes regulating this modification as prospective diagnostic biomarkers and therapeutic targets.
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Affiliation(s)
- Ying Wang
- The First Affiliated Hospital of Xinxiang Medical University, Xinxiang, Henan, PR China; Institute of Psychiatry and Neuroscience of Xinxiang Medical University, Xinxiang, Henan, PR China
| | - Haoyuan Ma
- Laboratory of Genetic Regulators in the Immune System, School of Medical Technology, Xinxiang Medical University, Xinxiang, Henan, PR China
| | - Bowen Zhang
- Laboratory of Genetic Regulators in the Immune System, School of Medical Technology, Xinxiang Medical University, Xinxiang, Henan, PR China
| | - Sainan Li
- Institute of Psychiatry and Neuroscience of Xinxiang Medical University, Xinxiang, Henan, PR China
| | - Beijia Lu
- Institute of Psychiatry and Neuroscience of Xinxiang Medical University, Xinxiang, Henan, PR China
| | - Yingcheng Qi
- Laboratory of Genetic Regulators in the Immune System, School of Medical Technology, Xinxiang Medical University, Xinxiang, Henan, PR China
| | - Tingting Liu
- Laboratory of Genetic Regulators in the Immune System, School of Medical Technology, Xinxiang Medical University, Xinxiang, Henan, PR China
| | - Hua Wang
- Department of Oncology, The First Affiliated Hospital of Anhui Medical University, Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Anhui Medical University, Hefei, Anhui, PR China.
| | - Xiaohong Kang
- The First Affiliated Hospital of Xinxiang Medical University, Xinxiang, Henan, PR China.
| | - Yinming Liang
- Laboratory of Genetic Regulators in the Immune System, School of Medical Technology, Xinxiang Medical University, Xinxiang, Henan, PR China.
| | - Eryan Kong
- The First Affiliated Hospital of Xinxiang Medical University, Xinxiang, Henan, PR China; Institute of Psychiatry and Neuroscience of Xinxiang Medical University, Xinxiang, Henan, PR China.
| | - Liu Cao
- Institute of Psychiatry and Neuroscience of Xinxiang Medical University, Xinxiang, Henan, PR China.
| | - Binhui Zhou
- The First Affiliated Hospital of Xinxiang Medical University, Xinxiang, Henan, PR China; Institute of Psychiatry and Neuroscience of Xinxiang Medical University, Xinxiang, Henan, PR China; Laboratory of Genetic Regulators in the Immune System, School of Medical Technology, Xinxiang Medical University, Xinxiang, Henan, PR China.
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Hossain MM, Mishra AK, Yadav AK, Ismail M, Sata TN, Sah AK, Banik A, Sharma G, Venugopal SK. Free fatty acid-induced DDX3 inhibits autophagy via miR-141 upregulation in diet-induced MASLD mice model system. Ann Hepatol 2024; 30:101758. [PMID: 39631458 DOI: 10.1016/j.aohep.2024.101758] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/13/2024] [Revised: 08/25/2024] [Accepted: 11/01/2024] [Indexed: 12/07/2024]
Abstract
INTRODUCTION AND OBJECTIVES Metabolic dysfunction-associated steatotic liver disease (MASLD) is one of the primary causes of chronic liver disease and may lead to liver cirrhosis and hepatocellular carcinoma. Recent reports suggested that DEAD-box RNA helicase (DDX3) acts as a sensor of free fat accumulation and may modulate the pathogenesis via miRNAs. Hence, we hypothesized that DDX3 might modulate MASLD progression via miRNA-141-mediated inhibition of Sirt-1 and autophagy. MATERIALS AND METHODS RNA and total protein were isolated from free fatty acid-treated HepG2 cells or CDAA-fed C57BL/6 mice (6 mice per group) for 6, 18, 32, or 54 weeks. The cells were transfected with DDX3 or miR-141 or siRNA to DDX3, and Western blots for autophagy markers were performed. RESULTS The FFAs induced the DDX3 and miRNA-141 expression, while downregulating Sirt-1, beclin-1, Atg7, and LC3-II. Overexpression of DDX3 resulted in increased miRNA-141. Overexpression of DDX3 or miRNA-141 downregulated Sirt-1 expression and autophagy marker proteins, while these effects were reversed with siRNA to DDX3. The expression of both DDX3 and miRNA-141 was significantly increased, while autophagy markers were downregulated in CDAA-fed mice. CONCLUSIONS These results confirmed that FFA-induced DDX3 induced the expression of miRNA-141, which in turn targeted Sirt-1 and decreased autophagy.
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Affiliation(s)
- Md Musa Hossain
- Faculty of Life Sciences and Biotechnology, South Asian University, New Delhi, India
| | - Amit K Mishra
- Department of Microbiology and Immunology, Albert Einstein College of Medicine, New York, USA
| | - Ajay K Yadav
- Department of Medical and Molecular genetics, Indiana University School of Medicine, Indianapolis, USA
| | - Md Ismail
- Faculty of Life Sciences and Biotechnology, South Asian University, New Delhi, India
| | - Teja Naveen Sata
- Faculty of Life Sciences and Biotechnology, South Asian University, New Delhi, India
| | - Amrendra K Sah
- Faculty of Life Sciences and Biotechnology, South Asian University, New Delhi, India
| | - Arnab Banik
- Faculty of Life Sciences and Biotechnology, South Asian University, New Delhi, India
| | - Gopal Sharma
- Faculty of Life Sciences and Biotechnology, South Asian University, New Delhi, India
| | - Senthil K Venugopal
- Faculty of Life Sciences and Biotechnology, South Asian University, New Delhi, India.
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Azariadis K, Gatselis NK, Lyberopoulou A, Arvaniti P, Zachou K, Gabeta S, Dalekos GN. PNPLA3 I148 M genetic variant in autoimmune hepatitis characterises advanced disease at diagnosis and reduced survival free of cirrhotic events and liver-related mortality. J Transl Autoimmun 2024; 9:100243. [PMID: 38974691 PMCID: PMC11225017 DOI: 10.1016/j.jtauto.2024.100243] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/27/2024] [Revised: 05/22/2024] [Accepted: 06/02/2024] [Indexed: 07/09/2024] Open
Abstract
Background Autoimmune hepatitis (AIH) is a relatively rare autoimmune disease with a strong genetic background. The patatin-like phospholipase domain-containing protein 3 (PNPLA3) I148 M (rs738409 C/G) variant has been associated with hepatic inflammation and fibrosis in chronic hepatic diseases beyond metabolic dysfunction-associated steatotic liver disease (MASLD). Aim Our aim was to investigate the significance of PNPLA3 I148 M variant in AIH. Method Two hundred AIH patients, followed in our centre, were evaluated while 100 healthy subjects served as controls. Genotyping was performed with allelic discrimination end-point polymerase chain reaction (PCR). Results The I148 M variant was present in 95/200 (47.5 %) AIH patients compared to 47/100 (47 %) healthy controls (p = 1.000). Patients with GG/CG genotypes were more likely to present with decompensated cirrhosis at diagnosis (GG/CG 6.3 % vs. CC 1 %, p = 0.039). Comorbidity with cardiometabolic risk factors and concurrence of MASLD was similar across genotypes. Simple steatosis was present in 37/186 (19.9 %) and steatohepatitis in 14/186 (7.5 %) patients with available liver biopsy without correlation with PNPLA3 genotype. Fibrosis stage and grade of inflammation were not correlated with any genotype. Response to treatment was also independent of the presence of the I148 M variant, even though a longer time was needed to achieve complete biochemical response in those carrying the GG/CG genotypes (p = 0.07). On Kaplan Meier analysis homozygosity for the G allele corelated with reduced survival free of decompensation (p = 0.006), cirrhotic events (decompensation, liver transplantation, hepatocellular carcinoma; p = 0.001) and liver-related death or liver transplantation (p = 0.011) in treated patients. Conclusions The PNPLA3 I148 M variant in AIH patients is associated with increased risk of advanced disease at diagnosis and reduced survival free of cirrhotic events and liver-related death or liver transplantation, regardless of the presence of MASLD. This signifies a potential role for the PNPLA3 I148 M variant as a new AIH biomarker allowing to identify patients at increased risk of disease progression.
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Affiliation(s)
- Kalliopi Azariadis
- Department of Medicine and Research Laboratory of Internal Medicine, National Expertise Center of Greece in Autoimmune Liver Diseases, General University Hospital of Larissa, Larissa, Greece
- European Reference Network on Hepatological Diseases (ERN Rare-Liver), General University Hospital of Larissa, Larissa, Greece
| | - Nikolaos K. Gatselis
- Department of Medicine and Research Laboratory of Internal Medicine, National Expertise Center of Greece in Autoimmune Liver Diseases, General University Hospital of Larissa, Larissa, Greece
- European Reference Network on Hepatological Diseases (ERN Rare-Liver), General University Hospital of Larissa, Larissa, Greece
| | - Aggeliki Lyberopoulou
- Department of Medicine and Research Laboratory of Internal Medicine, National Expertise Center of Greece in Autoimmune Liver Diseases, General University Hospital of Larissa, Larissa, Greece
- European Reference Network on Hepatological Diseases (ERN Rare-Liver), General University Hospital of Larissa, Larissa, Greece
| | - Pinelopi Arvaniti
- Department of Medicine and Research Laboratory of Internal Medicine, National Expertise Center of Greece in Autoimmune Liver Diseases, General University Hospital of Larissa, Larissa, Greece
- European Reference Network on Hepatological Diseases (ERN Rare-Liver), General University Hospital of Larissa, Larissa, Greece
| | - Kalliopi Zachou
- Department of Medicine and Research Laboratory of Internal Medicine, National Expertise Center of Greece in Autoimmune Liver Diseases, General University Hospital of Larissa, Larissa, Greece
- European Reference Network on Hepatological Diseases (ERN Rare-Liver), General University Hospital of Larissa, Larissa, Greece
| | - Stella Gabeta
- Department of Medicine and Research Laboratory of Internal Medicine, National Expertise Center of Greece in Autoimmune Liver Diseases, General University Hospital of Larissa, Larissa, Greece
- European Reference Network on Hepatological Diseases (ERN Rare-Liver), General University Hospital of Larissa, Larissa, Greece
| | - George N. Dalekos
- Department of Medicine and Research Laboratory of Internal Medicine, National Expertise Center of Greece in Autoimmune Liver Diseases, General University Hospital of Larissa, Larissa, Greece
- European Reference Network on Hepatological Diseases (ERN Rare-Liver), General University Hospital of Larissa, Larissa, Greece
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Fu S, Xu M, Li J, Yu M, Wang S, Han L, Li R, Deng F, Peng H, Liu D, Tan Y. HDAC6 inhibitor ACY-1215 protects from nonalcoholic fatty liver disease via inhibiting CD14/TLR4/MyD88/MAPK/NFκB signal pathway. Heliyon 2024; 10:e33740. [PMID: 39055804 PMCID: PMC11269855 DOI: 10.1016/j.heliyon.2024.e33740] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/04/2024] [Revised: 06/19/2024] [Accepted: 06/26/2024] [Indexed: 07/28/2024] Open
Abstract
BACKGROUND & AIMS Nonalcoholic fatty liver disease (NAFLD) is a chronic liver disease characterized by hepatic steatosis, for which there is currently no effective treatment. ACY-1215 is a selective inhibitor of histone deacetylation 6, which has shown therapeutic potential in many tumors, as well as acute liver injury. However, no research about ACY-1215 on NAFLD has been published. Therefore, our study aims to explore the role and mechanism of ACY-1215 in the experimental model of NAFLD, to propose a new treatment strategy for NAFLD. METHODS We established cell and animal models of NAFLD and verified the effect of ACY-1215 on NAFLD. The mechanism of ACY-1215 on NAFLD was preliminarily explored through TMT relative quantitative proteomics, and then we verify the mechanism discovered in the experimental model of NAFLD. RESULTS ACY-1215 can reduce lipid aggregation, IL-1β, and TNF α mRNA levels in liver cells in vitro. ACY-1215 can reduce the weight gain and steatosis in the liver of the NAFLD mouse model, alleviate the deterioration of liver function, and reduce IL-1βs and TNF α mRNA levels in hepatocytes. TMT relative quantitative proteomics found that ACY-1215 decreased the expression of CD14 in hepatocytes. It was found that ACY-1215 can inhibit the activation level of CD14/TLR4/MyD88/MAPK/NFκB pathway in the NAFLD experimental model. CONCLUSIONS ACY-1215 has a protective effect on the cellular model of NAFLD induced by fatty acids and lipopolysaccharide, as well as the C57BL/6J mouse model induced by a high-fat diet. ACY-1215 may play a protective role by inhibiting CD14/TLR4/MyD88/MAPK/NFκB signal pathway.
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Affiliation(s)
- Shifeng Fu
- Department of Gastroenterology, Second Xiangya Hospital, Central South University, Changsha, 410011, Hunan Province, China
- Research Center of Digestive Diseases, Central South University, Changsha, 410011, Hunan Province, China
- Clinical Research Center of Digestive Diseases of Hunan Province, Changsha, 410011, Hunan Province, China
| | - Mengmeng Xu
- Department of Gastroenterology, Second Xiangya Hospital, Central South University, Changsha, 410011, Hunan Province, China
- Research Center of Digestive Diseases, Central South University, Changsha, 410011, Hunan Province, China
- Clinical Research Center of Digestive Diseases of Hunan Province, Changsha, 410011, Hunan Province, China
| | - Jianglei Li
- Department of Gastroenterology, Second Xiangya Hospital, Central South University, Changsha, 410011, Hunan Province, China
- Research Center of Digestive Diseases, Central South University, Changsha, 410011, Hunan Province, China
- Clinical Research Center of Digestive Diseases of Hunan Province, Changsha, 410011, Hunan Province, China
| | - Meihong Yu
- Department of Gastroenterology, Second Xiangya Hospital, Central South University, Changsha, 410011, Hunan Province, China
- Research Center of Digestive Diseases, Central South University, Changsha, 410011, Hunan Province, China
- Clinical Research Center of Digestive Diseases of Hunan Province, Changsha, 410011, Hunan Province, China
| | - Siyi Wang
- Department of Gastroenterology, Second Xiangya Hospital, Central South University, Changsha, 410011, Hunan Province, China
- Research Center of Digestive Diseases, Central South University, Changsha, 410011, Hunan Province, China
- Clinical Research Center of Digestive Diseases of Hunan Province, Changsha, 410011, Hunan Province, China
| | - Liu Han
- Department of Gastroenterology, Second Xiangya Hospital, Central South University, Changsha, 410011, Hunan Province, China
- Research Center of Digestive Diseases, Central South University, Changsha, 410011, Hunan Province, China
- Clinical Research Center of Digestive Diseases of Hunan Province, Changsha, 410011, Hunan Province, China
| | - Rong Li
- Department of Gastroenterology, Second Xiangya Hospital, Central South University, Changsha, 410011, Hunan Province, China
- Research Center of Digestive Diseases, Central South University, Changsha, 410011, Hunan Province, China
- Clinical Research Center of Digestive Diseases of Hunan Province, Changsha, 410011, Hunan Province, China
| | - Feihong Deng
- Department of Gastroenterology, Second Xiangya Hospital, Central South University, Changsha, 410011, Hunan Province, China
- Research Center of Digestive Diseases, Central South University, Changsha, 410011, Hunan Province, China
- Clinical Research Center of Digestive Diseases of Hunan Province, Changsha, 410011, Hunan Province, China
| | - Hailing Peng
- Department of Gastroenterology, Second Xiangya Hospital, Central South University, Changsha, 410011, Hunan Province, China
- Research Center of Digestive Diseases, Central South University, Changsha, 410011, Hunan Province, China
- Clinical Research Center of Digestive Diseases of Hunan Province, Changsha, 410011, Hunan Province, China
- Longshan County People's Hospital, Longshan, 416899, Hunan Province, China
| | - Deliang Liu
- Department of Gastroenterology, Second Xiangya Hospital, Central South University, Changsha, 410011, Hunan Province, China
- Research Center of Digestive Diseases, Central South University, Changsha, 410011, Hunan Province, China
- Clinical Research Center of Digestive Diseases of Hunan Province, Changsha, 410011, Hunan Province, China
| | - Yuyong Tan
- Department of Gastroenterology, Second Xiangya Hospital, Central South University, Changsha, 410011, Hunan Province, China
- Research Center of Digestive Diseases, Central South University, Changsha, 410011, Hunan Province, China
- Clinical Research Center of Digestive Diseases of Hunan Province, Changsha, 410011, Hunan Province, China
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8
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Gan J, Shi Y, Zhao R, Li D, Jin H, Wu M, Liu Z, Li X, Xu A, Li Y, Lin Z, Wu F. Adipose c-Jun NH2-terminal kinase promotes angiotensin II-induced and deoxycorticosterone acetate salt-induced hypertension and vascular dysfunction by inhibition of adiponectin production and activation of SGK1 in mice. J Hypertens 2024; 42:856-872. [PMID: 38164960 DOI: 10.1097/hjh.0000000000003649] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/03/2024]
Abstract
BACKGROUND Adipose c-Jun NH2-terminal kinase 1/2 (JNK1/2) is a central mediator involved in the development of obesity and its complications. However, the roles of adipose JNK1/2 in hypertension remain elusive. Here we explored the role of adipose JNK1/2 in hypertension. METHODS AND RESULTS The roles of adipose JNK1/2 in hypertension were investigated by evaluating the impact of adipose JNK1/2 inactivation in both angiotensin II (Ang II)-induced and deoxycorticosterone acetate (DOCA) salt-induced hypertensive mice. Specific inactivation of JNK1/2 in adipocytes significantly alleviates Ang II-induced and DOCA salt-induced hypertension and target organ damage in mice. Interestingly, such beneficial effects are also observed in hypertensive mice after oral administration of JNK1/2 inhibitor SP600125. Mechanistically, adipose JNK1/2 acts on adipocytes to reduce the production of adiponectin (APN), then leads to promote serum and glucocorticoid-regulated kinase 1 (SGK1) phosphorylation and increases epithelial Na + channel α-subunit (ENaCα) expression in both renal cells and adipocytes, respectively, finally exacerbates Na + retention. In addition, chronic treatment of recombinant mouse APN significantly augments the beneficial effects of adipose JNK1/2 inactivation in DOCA salt-induced hypertension. By contrast, the blood pressure-lowering effects of adipose JNK1/2 inactivation are abrogated by adenovirus-mediated SGK1 overexpression in Ang II -treated adipose JNK1/2 inactivation mice. CONCLUSION Adipose JNK1/2 promotes hypertension and targets organ impairment via fine-tuning the multiorgan crosstalk among adipose tissue, kidney, and blood vessels.
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Affiliation(s)
- Jing Gan
- Department of Cardiology, the First Affiliated Hospital of Wenzhou Medical University
| | - Yaru Shi
- School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou
- Department of Pharmacy, the Sixth Affiliated Hospital of Wenzhou Medical University, Lishui
| | - Ruyi Zhao
- School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou
| | - Dan Li
- School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou
- Department of clinical pharmacy, the Forth People's Hospital of Liaocheng, Liaocheng
| | - Hua Jin
- School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou
| | - Maolan Wu
- School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou
| | - Zhen Liu
- School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou
| | - Xiaokun Li
- School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou
| | - Aimin Xu
- State Key Laboratory of Pharmaceutical Biotechnology, the University of Hong Kong, Hong Kong
| | - Yulin Li
- Beijing Institute of Heart, Lung, and Blood Vessel Diseases, Anzhen Hospital of Capital Medical University, Beijing
| | - Zhuofeng Lin
- Department of Cardiology, the First Affiliated Hospital of Wenzhou Medical University
- The laboratory of Animal Center, Wenzhou Medical University, Wenzhou, China
| | - Fan Wu
- School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou
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9
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Jung E, Baek EB, Hong EJ, Kang JH, Park S, Park S, Hong EJ, Cho YE, Ko JW, Won YS, Kwon HJ. TXNIP in liver sinusoidal endothelial cells ameliorates alcohol-associated liver disease via nitric oxide production. Int J Biol Sci 2024; 20:606-620. [PMID: 38169654 PMCID: PMC10758096 DOI: 10.7150/ijbs.90781] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/05/2023] [Accepted: 12/02/2023] [Indexed: 01/05/2024] Open
Abstract
Dysregulation of liver sinusoidal endothelial cell (LSEC) differentiation and function has been reported in alcohol-associated liver disease (ALD). Impaired nitric oxide (NO) production stimulates LSEC capillarization and dysfunction; however, the mechanism underlying NO production remains unclear. Here, we investigated the role of thioredoxin-interacting protein (TXNIP), an important regulator of redox homeostasis, in endothelial cell NO production and its subsequent effects on ALD progression. We found that hepatic TXNIP expression was upregulated in patients with ALD and in ethanol diet-fed mice with high expression in LSECs. Endothelial cell-specific Txnip deficiency (TxnipΔEC) in mice exacerbated alcohol-induced liver injury, inflammation, fibrosis, and hepatocellular carcinoma development. Deletion of Txnip in LSECs led to sinusoidal capillarization, downregulation of NO production, and increased release of proinflammatory cytokines and adhesion molecules, whereas TXNIP overexpression had the opposite effects. Mechanistically, TXNIP interacted with transforming growth factor β-activated kinase 1 (TAK1) and subsequently suppressed the TAK1 pathway. Inhibition of TAK1 activation restored NO production and decreased the levels of proinflammatory cytokines, thereby, blocking liver injury and inflammation in TxnipΔEC mice. Our findings indicate that upregulated TXNIP expression in LSECs serves a protective role in ameliorating ALD. Enhancing TXNIP expression could, therefore, be a potential therapeutic approach for ALD.
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Affiliation(s)
- Eunhye Jung
- College of Veterinary Medicine, Chungnam National University, Daejeon 34134, Republic of Korea
| | - Eun Bok Baek
- College of Veterinary Medicine, Chungnam National University, Daejeon 34134, Republic of Korea
| | - Eun-Ju Hong
- College of Veterinary Medicine, Chungnam National University, Daejeon 34134, Republic of Korea
| | - Jee Hyun Kang
- College of Veterinary Medicine, Chungnam National University, Daejeon 34134, Republic of Korea
| | - Suyoung Park
- College of Veterinary Medicine, Chungnam National University, Daejeon 34134, Republic of Korea
| | - Sehee Park
- Laboratory Animal Resource Center, Korea Research Institute of Bioscience and Biotechnology, Chungbuk 28116, Republic of Korea
| | - Eui-Ju Hong
- College of Veterinary Medicine, Chungnam National University, Daejeon 34134, Republic of Korea
| | - Young-Eun Cho
- Andong National University, Andong 36729, Republic of Korea
| | - Je-Won Ko
- College of Veterinary Medicine, Chungnam National University, Daejeon 34134, Republic of Korea
| | - Young-Suk Won
- Laboratory Animal Resource Center, Korea Research Institute of Bioscience and Biotechnology, Chungbuk 28116, Republic of Korea
| | - Hyo-Jung Kwon
- College of Veterinary Medicine, Chungnam National University, Daejeon 34134, Republic of Korea
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10
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Luo W, Gu Y, Fu S, Wang J, Zhang J, Wang Y. Emerging opportunities to treat idiopathic pulmonary fibrosis: Design, discovery, and optimizations of small-molecule drugs targeting fibrogenic pathways. Eur J Med Chem 2023; 260:115762. [PMID: 37683364 DOI: 10.1016/j.ejmech.2023.115762] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2023] [Revised: 08/15/2023] [Accepted: 08/23/2023] [Indexed: 09/10/2023]
Abstract
Idiopathic pulmonary fibrosis (IPF) is the most common fibrotic form of idiopathic diffuse lung disease. Due to limited treatment options, IPF patients suffer from poor survival. About ten years ago, Pirfenidone (Shionogi, 2008; InterMune, 2011) and Nintedanib (Boehringer Ingelheim, 2014) were approved, greatly changing the direction of IPF drug design. However, limited efficacy and side effects indicate that neither can reverse the process of IPF. With insights into the occurrence of IPF, novel targets and agents have been proposed, which have fundamentally changed the treatment of IPF. With the next-generation agents, targeting pro-fibrotic pathways in the epithelial-injury model offers a promising approach. Besides, several next-generation IPF drugs have entered phase II/III clinical trials with encouraging results. Due to the rising IPF treatment requirements, there is an urgent need to completely summarize the mechanisms, targets, problems, and drug design strategies over the past ten years. In this review, we summarize known mechanisms, target types, drug design, and novel technologies of IPF drug discovery, aiming to provide insights into the future development and clinical application of next-generation IPF drugs.
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Affiliation(s)
- Wenxin Luo
- Department of Pulmonary and Critical Care Medicine, Targeted Tracer Research and Development Laboratory, Institute of Respiratory Health, Frontiers Science Center for Disease-related Molecular Network, Precision Medicine Key Laboratory of Sichuan Province & Precision Medicine Research Center, Joint Research Institution of Altitude Health, National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, Chengdu, 610041, Sichuan, China
| | - Yilin Gu
- Department of Pulmonary and Critical Care Medicine, Targeted Tracer Research and Development Laboratory, Institute of Respiratory Health, Frontiers Science Center for Disease-related Molecular Network, Precision Medicine Key Laboratory of Sichuan Province & Precision Medicine Research Center, Joint Research Institution of Altitude Health, National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, Chengdu, 610041, Sichuan, China
| | - Siyu Fu
- Department of Pulmonary and Critical Care Medicine, Targeted Tracer Research and Development Laboratory, Institute of Respiratory Health, Frontiers Science Center for Disease-related Molecular Network, Precision Medicine Key Laboratory of Sichuan Province & Precision Medicine Research Center, Joint Research Institution of Altitude Health, National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, Chengdu, 610041, Sichuan, China
| | - Jiaxing Wang
- Department of Pharmaceutical Sciences, College of Pharmacy, University of Tennessee Health Science Center, Memphis, 38163, Tennessee, United States
| | - Jifa Zhang
- Department of Pulmonary and Critical Care Medicine, Targeted Tracer Research and Development Laboratory, Institute of Respiratory Health, Frontiers Science Center for Disease-related Molecular Network, Precision Medicine Key Laboratory of Sichuan Province & Precision Medicine Research Center, Joint Research Institution of Altitude Health, National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, Chengdu, 610041, Sichuan, China; Frontiers Medical Center, Tianfu Jincheng Laboratory, Chengdu, 610212, Sichuan, China.
| | - Yuxi Wang
- Department of Pulmonary and Critical Care Medicine, Targeted Tracer Research and Development Laboratory, Institute of Respiratory Health, Frontiers Science Center for Disease-related Molecular Network, Precision Medicine Key Laboratory of Sichuan Province & Precision Medicine Research Center, Joint Research Institution of Altitude Health, National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, Chengdu, 610041, Sichuan, China; Frontiers Medical Center, Tianfu Jincheng Laboratory, Chengdu, 610212, Sichuan, China.
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11
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Ding Y, Dai X, Bao M, Xing Y, Liu J, Zhao S, Liu E, Yuan Z, Bai L. Hepatic transcriptome signatures in mice and humans with nonalcoholic fatty liver disease. Animal Model Exp Med 2023; 6:317-328. [PMID: 37565549 PMCID: PMC10486336 DOI: 10.1002/ame2.12338] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/20/2023] [Accepted: 07/12/2023] [Indexed: 08/12/2023] Open
Abstract
BACKGROUND Nonalcoholic fatty liver disease (NAFLD) is the main reason for cirrhosis and hepatocellular carcinoma. As a starting point for NAFLD, the treatment of nonalcoholic fatty liver (NAFL) is receiving increasing attention. Mice fed a high-fat diet (HFD) and hereditary leptin deficiency (ob/ob) mice are important NAFL animal models. However, the comparison of these mouse models with human NAFL is still unclear. METHODS In this study, HFD-fed mice and ob/ob mice were used as NAFL animal models. Liver histopathological characteristics were compared, and liver transcriptome from both mouse models was performed using RNA sequencing (RNA-seq). RNA-seq data obtained from the livers of NAFL patients was downloaded from the GEO database. Global gene expression profiles in the livers were further analyzed using functional enrichment analysis and the Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway. RESULTS Our results showed that the biochemical parameters of both mouse models and human NAFL were similar. Compared with HFD-fed mice, ob/ob mice were more similar in histologic appearance to NAFL patients. The liver transcriptome characteristics partly overlapped in mice and humans. Furthermore, in the NAFL pathway, most genes showed similar trends in mice and humans, thus demonstrating that both types of mice can be used as models for basic research on NAFL, considering the differences. CONCLUSION Our findings show that HFD-fed mice and ob/ob mice can mimic human NAFL partly in pathophysiological process. The comparative analysis of liver transcriptome profile in mouse models and human NAFL presented here provides insights into the molecular characteristics across these NAFL models.
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Affiliation(s)
- Yiming Ding
- Department of Laboratory Animal Science, School of Basic Medical SciencesXi'an Jiaotong University Health Science CenterXi'anChina
- Department of CardiologyFirst Affiliated Hospital of Xi'an Jiaotong UniversityXi'anChina
- Institute of Cardiovascular Science, Translational Medicine InstituteXi'an Jiaotong University Health Science CenterXi'anChina
| | - Xulei Dai
- Department of Laboratory Animal Science, School of Basic Medical SciencesXi'an Jiaotong University Health Science CenterXi'anChina
- Institute of Cardiovascular Science, Translational Medicine InstituteXi'an Jiaotong University Health Science CenterXi'anChina
| | - Miaoye Bao
- Department of Laboratory Animal Science, School of Basic Medical SciencesXi'an Jiaotong University Health Science CenterXi'anChina
- Institute of Cardiovascular Science, Translational Medicine InstituteXi'an Jiaotong University Health Science CenterXi'anChina
| | - Yuanming Xing
- Department of CardiologyFirst Affiliated Hospital of Xi'an Jiaotong UniversityXi'anChina
- Institute of Cardiovascular Science, Translational Medicine InstituteXi'an Jiaotong University Health Science CenterXi'anChina
| | - Junhui Liu
- Department of Clinical LaboratoryFirst Affiliated Hospital of Xi'an Jiaotong UniversityXi'anChina
| | - Sihai Zhao
- Department of Laboratory Animal Science, School of Basic Medical SciencesXi'an Jiaotong University Health Science CenterXi'anChina
- Institute of Cardiovascular Science, Translational Medicine InstituteXi'an Jiaotong University Health Science CenterXi'anChina
| | - Enqi Liu
- Department of Laboratory Animal Science, School of Basic Medical SciencesXi'an Jiaotong University Health Science CenterXi'anChina
- Institute of Cardiovascular Science, Translational Medicine InstituteXi'an Jiaotong University Health Science CenterXi'anChina
| | - Zuyi Yuan
- Department of CardiologyFirst Affiliated Hospital of Xi'an Jiaotong UniversityXi'anChina
| | - Liang Bai
- Department of Laboratory Animal Science, School of Basic Medical SciencesXi'an Jiaotong University Health Science CenterXi'anChina
- Institute of Cardiovascular Science, Translational Medicine InstituteXi'an Jiaotong University Health Science CenterXi'anChina
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12
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Fang J, Celton-Morizur S, Desdouets C. NAFLD-Related HCC: Focus on the Latest Relevant Preclinical Models. Cancers (Basel) 2023; 15:3723. [PMID: 37509384 PMCID: PMC10377912 DOI: 10.3390/cancers15143723] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/16/2023] [Revised: 07/17/2023] [Accepted: 07/18/2023] [Indexed: 07/30/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is the most common type of primary liver cancer and one of the deadliest cancers worldwide. Despite extensive research, the biological mechanisms underlying HCC's development and progression remain only partially understood. Chronic overeating and/or sedentary-lifestyle-associated obesity, which promote Non-Alcoholic Fatty Liver Disease (NAFLD), have recently emerged as worrying risk factors for HCC. NAFLD is characterized by excessive hepatocellular lipid accumulation (steatosis) and affects one quarter of the world's population. Steatosis progresses in the more severe inflammatory form, Non-Alcoholic Steatohepatitis (NASH), potentially leading to HCC. The incidence of NASH is expected to increase by up to 56% over the next 10 years. Better diagnoses and the establishment of effective treatments for NAFLD and HCC will require improvements in our understanding of the fundamental mechanisms of the disease's development. This review describes the pathogenesis of NAFLD and the mechanisms underlying the transition from NAFL/NASH to HCC. We also discuss a selection of appropriate preclinical models of NAFLD for research, from cellular models such as liver-on-a-chip models to in vivo models, focusing particularly on mouse models of dietary NAFLD-HCC.
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Affiliation(s)
- Jing Fang
- Centre de Recherche des Cordeliers, INSERM, Sorbonne Université, Université de Paris, 75006 Paris, France
- Genomic Instability, Metabolism, Immunity and Liver Tumorigenesis Laboratory, Equipe Labellisée Ligue Contre le Cancer, 75005 Paris, France
| | - Séverine Celton-Morizur
- Centre de Recherche des Cordeliers, INSERM, Sorbonne Université, Université de Paris, 75006 Paris, France
- Genomic Instability, Metabolism, Immunity and Liver Tumorigenesis Laboratory, Equipe Labellisée Ligue Contre le Cancer, 75005 Paris, France
| | - Chantal Desdouets
- Centre de Recherche des Cordeliers, INSERM, Sorbonne Université, Université de Paris, 75006 Paris, France
- Genomic Instability, Metabolism, Immunity and Liver Tumorigenesis Laboratory, Equipe Labellisée Ligue Contre le Cancer, 75005 Paris, France
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13
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Alabdulaali B, Al-rashed F, Al-Onaizi M, Kandari A, Razafiarison J, Tonui D, Williams MR, Blériot C, Ahmad R, Alzaid F. Macrophages and the development and progression of non-alcoholic fatty liver disease. Front Immunol 2023; 14:1195699. [PMID: 37377968 PMCID: PMC10291618 DOI: 10.3389/fimmu.2023.1195699] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/28/2023] [Accepted: 05/31/2023] [Indexed: 06/29/2023] Open
Abstract
The liver is the site of first pass metabolism, detoxifying and metabolizing blood arriving from the hepatic portal vein and hepatic artery. It is made up of multiple cell types, including macrophages. These are either bona fide tissue-resident Kupffer cells (KC) of embryonic origin, or differentiated from circulating monocytes. KCs are the primary immune cells populating the liver under steady state. Liver macrophages interact with hepatocytes, hepatic stellate cells, and liver sinusoidal endothelial cells to maintain homeostasis, however they are also key contributors to disease progression. Generally tolerogenic, they physiologically phagocytose foreign particles and debris from portal circulation and participate in red blood cell clearance. However as immune cells, they retain the capacity to raise an alarm to recruit other immune cells. Their aberrant function leads to the development of non-alcoholic fatty liver disease (NAFLD). NAFLD refers to a spectrum of conditions ranging from benign steatosis of the liver to steatohepatitis and cirrhosis. In NAFLD, the multiple hit hypothesis proposes that simultaneous influences from the gut and adipose tissue (AT) generate hepatic fat deposition and that inflammation plays a key role in disease progression. KCs initiate the inflammatory response as resident immune effectors, they signal to neighbouring cells and recruit monocytes that differentiated into recruited macrophages in situ. Recruited macrophages are central to amplifying the inflammatory response and causing progression of NAFLD to its fibro-inflammatory stages. Given their phagocytic capacity and their being instrumental in maintaining tissue homeostasis, KCs and recruited macrophages are fast-becoming target cell types for therapeutic intervention. We review the literature in the field on the roles of these cells in the development and progression of NAFLD, the characteristics of patients with NAFLD, animal models used in research, as well as the emerging questions. These include the gut-liver-brain axis, which when disrupted can contribute to decline in function, and a discussion on therapeutic strategies that act on the macrophage-inflammatory axis.
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Affiliation(s)
- Bader Alabdulaali
- Dasman Diabetes Institute, Kuwait City, Kuwait
- Ministry of Health, Kuwait City, Kuwait
| | | | - Mohammed Al-Onaizi
- Dasman Diabetes Institute, Kuwait City, Kuwait
- Department of Anatomy, Faculty of Medicine, Kuwait University, Kuwait City, Kuwait
| | - Anwar Kandari
- Dasman Diabetes Institute, Kuwait City, Kuwait
- Ministry of Health, Kuwait City, Kuwait
| | - Joanna Razafiarison
- INSERM UMR-S1151, CNRS UMR-S8253, Université Paris Cité, Institut Necker Enfants Malades, Paris, France
| | - Dorothy Tonui
- INSERM UMR-S1151, CNRS UMR-S8253, Université Paris Cité, Institut Necker Enfants Malades, Paris, France
| | | | - Camille Blériot
- INSERM UMR-S1151, CNRS UMR-S8253, Université Paris Cité, Institut Necker Enfants Malades, Paris, France
- Inserm U1015, Gustave Roussy, Villejuif, France
| | | | - Fawaz Alzaid
- Dasman Diabetes Institute, Kuwait City, Kuwait
- INSERM UMR-S1151, CNRS UMR-S8253, Université Paris Cité, Institut Necker Enfants Malades, Paris, France
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14
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das Neves RX, Yamashita AS, Riccardi DMR, Köhn-Gaone J, Camargo RG, Neto NI, Caetano D, Gomes SP, Santos FH, Lima JDCC, Batista ML, Rosa-Neto JC, Martins De Alcântara PS, Maximiano LF, Otoch JP, Trinchieri G, Tirnitz-Parker JEE, Seelaender M. Cachexia causes time-dependent activation of the inflammasome in the liver. J Cachexia Sarcopenia Muscle 2023. [PMID: 37177862 PMCID: PMC10401524 DOI: 10.1002/jcsm.13236] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/07/2022] [Revised: 03/01/2023] [Accepted: 03/15/2023] [Indexed: 05/15/2023] Open
Abstract
BACKGROUND Cachexia is a wasting syndrome associated with systemic inflammation and metabolic disruption. Detection of the early signs of the disease may contribute to the effective attenuation of associated symptoms. Despite playing a central role in the control of metabolism and inflammation, the liver has received little attention in cachexia. We previously described relevant disruption of metabolic pathways in the organ in an animal model of cachexia, and herein, we adopt the same model to investigate temporal onset of inflammation in the liver. The aim was thus to study inflammation in rodent liver in the well-characterized cachexia model of Walker 256 carcinosarcoma and, in addition, to describe inflammatory alterations in the liver of one cachectic colon cancer patient, as compared to one control and one weight-stable cancer patient. METHODS Colon cancer patients (one weight stable [WSC] and one cachectic [CC]) and one patient undergoing surgery for cholelithiasis (control, n = 1) were enrolled in the study, after obtainment of fully informed consent. Eight-week-old male rats were subcutaneously inoculated with a Walker 256 carcinosarcoma cell suspension (2 × 107 cells in 1.0 mL; tumour-bearing [T]; or phosphate-buffered saline-controls [C]). The liver was excised on Days 0 (n = 5), 7 (n = 5) and 14 (n = 5) after tumour cell injection. RESULTS In rodent cachexia, we found progressively higher numbers of CD68+ myeloid cells in the liver along cancer-cachexia development. Similar findings are described for CC, whose liver showed infiltration of the same cell type, compared with both WSC and control patient organs. In advanced rodent cachexia, hepatic phosphorylated c-Jun N-terminal kinase protein content and the inflammasome pathway protein expression were increased in relation to baseline (P < 0.05). These changes were accompanied by augmented expression of the active interleukin-1β (IL-1β) form (P < 0.05 for both circulating and hepatic content). CONCLUSIONS The results show that cancer cachexia is associated with an increase in the number of myeloid cells in rodent and human liver and with modulation of hepatic inflammasome pathway. The latter contributes to the aggravation of systemic inflammation, through increased release of IL-1β.
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Affiliation(s)
- Rodrigo Xavier das Neves
- Cancer Metabolism Research Group, Department of Surgery and LIM26-HCFMUSP Faculdade de Medicina, University of São Paulo, São Paulo, Brazil
- LICI, Center for Cancer Research, National Cancer Institute, Bethesda, MD, USA
| | - Alex S Yamashita
- Department of Physiology and Biophysics, Institute of Biomedical Sciences, University of São Paulo, São Paulo, Brazil
| | - Daniela M R Riccardi
- Cancer Metabolism Research Group, Department of Surgery and LIM26-HCFMUSP Faculdade de Medicina, University of São Paulo, São Paulo, Brazil
| | - Julia Köhn-Gaone
- Department of Surgery, School of Veterinary Medicine and Animal Science of University of São Paulo-FMVZ/USP, São Paulo, Brazil
| | - Rodolfo G Camargo
- Cancer Metabolism Research Group, Department of Surgery and LIM26-HCFMUSP Faculdade de Medicina, University of São Paulo, São Paulo, Brazil
| | - Nelson I Neto
- Department of Physiology, Federal University of São Paulo, São Paulo, Brazil
| | - Daniela Caetano
- Cancer Metabolism Research Group, Department of Surgery and LIM26-HCFMUSP Faculdade de Medicina, University of São Paulo, São Paulo, Brazil
| | - Silvio P Gomes
- Cancer Metabolism Research Group, Department of Surgery and LIM26-HCFMUSP Faculdade de Medicina, University of São Paulo, São Paulo, Brazil
- Department of Surgery, School of Veterinary Medicine and Animal Science of University of São Paulo-FMVZ/USP, São Paulo, Brazil
| | - Felipe H Santos
- Laboratory of Adipose Tissue Biology, Center for Integrated Biotechnology, University of Mogi das Cruzes, São Paulo, Brazil
| | - Joanna D C C Lima
- Cancer Metabolism Research Group, Department of Surgery and LIM26-HCFMUSP Faculdade de Medicina, University of São Paulo, São Paulo, Brazil
| | - Miguel L Batista
- Laboratory of Adipose Tissue Biology, Center for Integrated Biotechnology, University of Mogi das Cruzes, São Paulo, Brazil
| | - José Cesar Rosa-Neto
- Immunometabolism Research Group, Department of Cell and Developmental Biology, Institute of Biomedical Sciences, University of São Paulo, São Paulo, Brazil
| | - Paulo Sérgio Martins De Alcântara
- Cancer Metabolism Research Group, Department of Surgery and LIM26-HCFMUSP Faculdade de Medicina, University of São Paulo, São Paulo, Brazil
| | - Linda F Maximiano
- Cancer Metabolism Research Group, Department of Surgery and LIM26-HCFMUSP Faculdade de Medicina, University of São Paulo, São Paulo, Brazil
| | - José P Otoch
- LICI, Center for Cancer Research, National Cancer Institute, Bethesda, MD, USA
| | - Giorgio Trinchieri
- LICI, Center for Cancer Research, National Cancer Institute, Bethesda, MD, USA
| | - Janina E E Tirnitz-Parker
- Liver Disease and Regeneration Laboratory, School of Pharmacy and Biomedical Sciences and Curtin Health Innovation Research Institute, Curtin University, Bentley, Western Australia, Australia
| | - Marília Seelaender
- Cancer Metabolism Research Group, Department of Surgery and LIM26-HCFMUSP Faculdade de Medicina, University of São Paulo, São Paulo, Brazil
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15
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Torosian K, Lal E, Kavanaugh A, Loomba R, Ajmera V, Guma M. Psoriatic disease and non-alcoholic fatty liver disease shared pathogenesis review. Semin Arthritis Rheum 2023; 59:152165. [PMID: 36716599 PMCID: PMC9992353 DOI: 10.1016/j.semarthrit.2023.152165] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2022] [Revised: 12/03/2022] [Accepted: 01/04/2023] [Indexed: 01/20/2023]
Abstract
Psoriatic disease (PD) and non-alcoholic fatty liver disease (NAFLD) potentially share disease pathways given the numerous inflammatory pathways involved in both diseases and a higher prevalence of NAFLD in PD patients. Metabolic syndrome and obesity are a key link between the two diseases, but even when controlling for this, associations between both diseases are still seen. Therapeutics that impact metabolic or inflammatory pathways may be impactful in both PD and NAFLD. In this review, we describe common inflammatory pathways contributing to both PD and NAFLD and critically review the potential impact of treatments for and on both diseases.
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Affiliation(s)
- Kelly Torosian
- Department of Medicine, School of Medicine, University of California, San Diego, 9500 Gilman Drive, San Diego, CA 92093, USA
| | - Esha Lal
- Department of Medicine, School of Medicine, University of California, San Diego, 9500 Gilman Drive, San Diego, CA 92093, USA
| | - Arthur Kavanaugh
- Department of Rheumatology, University of California, San Diego, 9500 Gilman Drive, San Diego, CA 92093, USA
| | - Rohit Loomba
- Division of Gastroenterology and Hepatology, University of California, San Diego, 9500 Gilman Drive, San Diego, CA 92093, USA; NAFLD Research Center, Department of Medicine, University of California at San Diego, La Jolla, USA; Division of Epidemiology, Department of Family and Preventative Medicine, University of California at San Diego, La Jolla, USA
| | - Veeral Ajmera
- Division of Gastroenterology and Hepatology, University of California, San Diego, 9500 Gilman Drive, San Diego, CA 92093, USA; NAFLD Research Center, Department of Medicine, University of California at San Diego, La Jolla, USA.
| | - Monica Guma
- Department of Rheumatology, University of California, San Diego, 9500 Gilman Drive, San Diego, CA 92093, USA; Department of Medicine, Autonomous University of Barcelona, Plaça Cívica, 08193 Bellaterra, Barcelona, Spain; San Diego VA Healthcare Service, San Diego, CA, 92161, USA.
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16
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Guha Ray A, Odum OP, Wiseman D, Weinstock A. The diverse roles of macrophages in metabolic inflammation and its resolution. Front Cell Dev Biol 2023; 11:1147434. [PMID: 36994095 PMCID: PMC10041730 DOI: 10.3389/fcell.2023.1147434] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/18/2023] [Accepted: 02/14/2023] [Indexed: 03/14/2023] Open
Abstract
Macrophages are one of the most functionally diverse immune cells, indispensable to maintain tissue integrity and metabolic health. Macrophages perform a myriad of functions ranging from promoting inflammation, through inflammation resolution to restoring and maintaining tissue homeostasis. Metabolic diseases encompass a growing list of diseases which develop from a mix of genetics and environmental cues leading to metabolic dysregulation and subsequent inflammation. In this review, we summarize the contributions of macrophages to four metabolic conditions-insulin resistance and adipose tissue inflammation, atherosclerosis, non-alcoholic fatty liver disease and neurodegeneration. The role of macrophages is complex, yet they hold great promise as potential therapies to address these growing health concerns.
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Affiliation(s)
| | | | | | - Ada Weinstock
- Section of Genetic Medicine, Department of Medicine, The University of Chicago, Chicago, IL, United States
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17
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Reolizo L, Matsuda M, Seki E. Experimental Workflow for Preclinical Studies of Human Antifibrotic Therapies. Methods Mol Biol 2023; 2669:285-306. [PMID: 37247068 DOI: 10.1007/978-1-0716-3207-9_18] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 05/30/2023]
Abstract
Chronic liver diseases accompanied by liver fibrosis have caused significant morbidity and mortality in the world with increasing prevalence. Nonetheless, there are no approved antifibrotic therapies. Although numerous preclinical studies showed satisfactory results in targeting fibrotic pathways, these animal studies have not led to success in humans. In this chapter, we summarize the experimental approaches currently available, including in vitro cell culture models, in vivo animal models, and new experimental tools relevant to humans, and discuss how we translate laboratory results to clinical trials. We will also address the obstacles in transitioning promising therapies from preclinical studies to human antifibrotic treatments.
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Affiliation(s)
- Lien Reolizo
- Karsh Division of Gastroenterology and Hepatology, Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, CA, USA
| | - Michitaka Matsuda
- Karsh Division of Gastroenterology and Hepatology, Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, CA, USA
| | - Ekihiro Seki
- Karsh Division of Gastroenterology and Hepatology, Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, CA, USA.
- Department of Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, CA, USA.
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18
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Flessa CM, Nasiri-Ansari N, Kyrou I, Leca BM, Lianou M, Chatzigeorgiou A, Kaltsas G, Kassi E, Randeva HS. Genetic and Diet-Induced Animal Models for Non-Alcoholic Fatty Liver Disease (NAFLD) Research. Int J Mol Sci 2022; 23:15791. [PMID: 36555433 PMCID: PMC9780957 DOI: 10.3390/ijms232415791] [Citation(s) in RCA: 54] [Impact Index Per Article: 18.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/02/2022] [Revised: 12/05/2022] [Accepted: 12/10/2022] [Indexed: 12/15/2022] Open
Abstract
A rapidly increasing incidence of non-alcoholic fatty liver disease (NAFLD) is noted worldwide due to the adoption of western-type lifestyles and eating habits. This makes the understanding of the molecular mechanisms that drive the pathogenesis of this chronic disease and the development of newly approved treatments of utmost necessity. Animal models are indispensable tools for achieving these ends. Although the ideal mouse model for human NAFLD does not exist yet, several models have arisen with the combination of dietary interventions, genetic manipulations and/or administration of chemical substances. Herein, we present the most common mouse models used in the research of NAFLD, either for the whole disease spectrum or for a particular disease stage (e.g., non-alcoholic steatohepatitis). We also discuss the advantages and disadvantages of each model, along with the challenges facing the researchers who aim to develop and use animal models for translational research in NAFLD. Based on these characteristics and the specific study aims/needs, researchers should select the most appropriate model with caution when translating results from animal to human.
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Affiliation(s)
- Christina-Maria Flessa
- Department of Biological Chemistry, Medical School, National and Kapodistrian University of Athens, 11527 Athens, Greece
- Warwickshire Institute for the Study of Diabetes, Endocrinology and Metabolism (WISDEM), University Hospitals Coventry and Warwickshire NHS Trust, Coventry CV2 2DX, UK
| | - Narjes Nasiri-Ansari
- Department of Biological Chemistry, Medical School, National and Kapodistrian University of Athens, 11527 Athens, Greece
| | - Ioannis Kyrou
- Warwickshire Institute for the Study of Diabetes, Endocrinology and Metabolism (WISDEM), University Hospitals Coventry and Warwickshire NHS Trust, Coventry CV2 2DX, UK
- Warwick Medical School, University of Warwick, Coventry CV4 7AL, UK
- Research Institute for Health and Wellbeing, Coventry University, Coventry CV1 5FB, UK
- Aston Medical School, College of Health and Life Sciences, Aston University, Birmingham B4 7ET, UK
- Laboratory of Dietetics and Quality of Life, Department of Food Science and Human Nutrition, School of Food and Nutritional Sciences, Agricultural University of Athens, 11855 Athens, Greece
| | - Bianca M. Leca
- Warwickshire Institute for the Study of Diabetes, Endocrinology and Metabolism (WISDEM), University Hospitals Coventry and Warwickshire NHS Trust, Coventry CV2 2DX, UK
| | - Maria Lianou
- Department of Biological Chemistry, Medical School, National and Kapodistrian University of Athens, 11527 Athens, Greece
| | - Antonios Chatzigeorgiou
- Department of Physiology, Medical School, National and Kapodistrian University of Athens, 11527 Athens, Greece
| | - Gregory Kaltsas
- Endocrine Unit, 1st Department of Propaedeutic Internal Medicine, Laiko Hospital, National and Kapodistrian University of Athens, 11527 Athens, Greece
| | - Eva Kassi
- Department of Biological Chemistry, Medical School, National and Kapodistrian University of Athens, 11527 Athens, Greece
- Endocrine Unit, 1st Department of Propaedeutic Internal Medicine, Laiko Hospital, National and Kapodistrian University of Athens, 11527 Athens, Greece
| | - Harpal S. Randeva
- Warwickshire Institute for the Study of Diabetes, Endocrinology and Metabolism (WISDEM), University Hospitals Coventry and Warwickshire NHS Trust, Coventry CV2 2DX, UK
- Warwick Medical School, University of Warwick, Coventry CV4 7AL, UK
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19
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Che W, Zhao M, Li X, Li C, Cho WC, Yu S. Current insights in molecular characterization of non-alcoholic fatty liver disease and treatment. Front Endocrinol (Lausanne) 2022; 13:1002916. [PMID: 36523601 PMCID: PMC9744925 DOI: 10.3389/fendo.2022.1002916] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/25/2022] [Accepted: 10/14/2022] [Indexed: 11/30/2022] Open
Abstract
There is a continuously rising incidence of non-alcoholic fatty liver disease (NAFLD) around the world, which parallels the increasing incidence of metabolic diseases. NAFLD is a range of liver conditions that contains simple non-alcoholic fatty liver and advanced non-alcoholic steatohepatitis. In serious cases, NAFLD may develop into cirrhosis or even liver cancer. NAFLD has an intense relationship with metabolic syndrome, type 2 diabetes mellitus. It is known that gut microbiota, and functional molecules such as adenosine monophosphate-activated protein kinase JNK, and peroxisome proliferator-activated receptors (PPARs) in progressing and treating NAFLD. Traditionally, the conventional and effective therapeutic strategy is lifestyle intervention. Nowadays, new medicines targeting specific molecules, such as farnesoid X receptor, PPARs, and GLP-1 receptor, have been discovered and shown beneficial effects on patients with NAFLD. In this article, we focus on the molecular mechanisms and therapeutic approaches to NAFLD.
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Affiliation(s)
- Wensheng Che
- Department of General Surgery, The Second Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Ming Zhao
- Chengdu Medical College, Chengdu, China
- Department of Gastroenterology, The First Affiliated Hospital of Chengdu Medical College, Chengdu, China
| | - Xiaoqing Li
- Department of Pathology, The Second Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Chunlong Li
- Department of General Surgery, The Second Affiliated Hospital of Harbin Medical University, Harbin, China
| | - William C. Cho
- Department of Clinical Oncology, Queen Elizabeth Hospital, Kowloon, Hong Kong SAR, China
| | - Shan Yu
- Department of Pathology, The Second Affiliated Hospital of Harbin Medical University, Harbin, China
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20
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Phung HH, Lee CH. Mouse models of nonalcoholic steatohepatitis and their application to new drug development. Arch Pharm Res 2022; 45:761-794. [DOI: 10.1007/s12272-022-01410-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/02/2022] [Accepted: 10/10/2022] [Indexed: 11/05/2022]
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Laursen TL, Mellemkjær A, Møller HJ, Grønbæk H, Kazankov K. Spotlight on liver macrophages for halting injury and progression in non-alcoholic fatty liver disease. Expert Opin Ther Targets 2022; 26:697-705. [PMID: 36205054 DOI: 10.1080/14728222.2022.2132145] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/09/2022]
Abstract
INTRODUCTION Non-alcoholic fatty liver disease (NAFLD) is considered the hepatic manifestation of the metabolic syndrome and is rapidly emerging as the leading cause of liver-related morbidity and mortality. Macrophages play an essential role in the development and progression of NAFLD. AREAS COVERED In this review, we provide an update on recent studies of drugs, which directly or indirectly affect macrophages in NAFLD, and discuss the implication of macrophage biomarkers to monitor the disease stage and progression/regression. EXPERT OPINION There is an unmet need for better understanding of disease pathogenesis from hepatic fat accumulation to disease progression with inflammation and fibrosis. We expect that future research will uncover additional objects/pathways as treatment targets. We speculate that this will involve better characterization of the gut microbiome, damage-associated molecular patterns (DAMPS) or molecules and pathways involved in development of DAMPS, and advanced molecular biology studies including single-cell sequencing of macrophage subpopulations. In addition, we speculate that studies focusing on pharmaceuticals that improve insulin resistance, diminish the metabolic syndrome and reduce fibrosis will prevail.
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Affiliation(s)
- Tea Lund Laursen
- Department of Medicine, Randers Regional Hospital, Randers, Denmark
| | - Anders Mellemkjær
- Department of Hepatology and Gastroenterology, Aarhus University Hospital, Aarhus, Denmark
| | - Holger Jon Møller
- Department of Clinical Biochemistry, Aarhus University Hospital, Aarhus, Denmark
| | - Henning Grønbæk
- Department of Hepatology and Gastroenterology, Aarhus University Hospital, Aarhus, Denmark
| | - Konstantin Kazankov
- Department of Hepatology and Gastroenterology, Aarhus University Hospital, Aarhus, Denmark
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22
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Li Y, Jiang JX, Fan W, Fish SR, Das S, Gupta P, Mozes G, Vancza L, Sarkar S, Kunimoto K, Chen D, Park H, Clemens D, Tomilov A, Cortopassi G, Török NJ. Shc Is Implicated in Calreticulin-Mediated Sterile Inflammation in Alcoholic Hepatitis. Cell Mol Gastroenterol Hepatol 2022; 15:197-211. [PMID: 36122677 PMCID: PMC9676381 DOI: 10.1016/j.jcmgh.2022.09.005] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/29/2021] [Revised: 09/12/2022] [Accepted: 09/12/2022] [Indexed: 12/23/2022]
Abstract
BACKGROUND & AIMS Src homology and collagen (Shc) proteins are major adapters to extracellular signals, however, the regulatory role of Shc isoforms in sterile inflammatory responses in alcoholic hepatitis (AH) has not been fully investigated. We hypothesized that in an isoform-specific manner Shc modulates pre-apoptotic signals, calreticulin (CRT) membrane exposure, and recruitment of inflammatory cells. METHODS Liver biopsy samples from patients with AH vs healthy subjects were studied for Shc expression using DNA microarray data and immunohistochemistry. Shc knockdown (hypomorph) and age-matched wild-type mice were pair-fed according to the chronic-plus-binge alcohol diet. To analyze hepatocyte-specific effects, adeno-associated virus 8-thyroxine binding globulin-Cre (hepatocyte-specific Shc knockout)-mediated deletion was performed in flox/flox Shc mice. Lipid peroxidation, proinflammatory signals, redox radicals, reduced nicotinamide adenine dinucleotide/oxidized nicotinamide adenine dinucleotide ratio, as well as cleaved caspase 8, B-cell-receptor-associated protein 31 (BAP31), Bcl-2-associated X protein (Bax), and Bcl-2 homologous antagonist killer (Bak), were assessed in vivo. CRT translocation was studied in ethanol-exposed p46ShcẟSH2-transfected hepatocytes by membrane biotinylation in conjunction with phosphorylated-eukaryotic initiation factor 2 alpha, BAP31, caspase 8, and Bax/Bak. The effects of idebenone, a novel Shc inhibitor, was studied in alcohol/pair-fed mice. RESULTS Shc was significantly induced in patients with AH (P < .01). Alanine aminotransferase, reduced nicotinamide adenine dinucleotide/oxidized nicotinamide adenine dinucleotide ratios, production of redox radicals, and lipid peroxidation improved (P < .05), and interleukin 1β, monocyte chemoattractant protein 1, and C-X-C chemokine ligand 10 were reduced in Shc knockdown and hepatocyte-specific Shc knockout mice. In vivo, Shc-dependent induction, and, in hepatocytes, a p46Shc-dependent increase in pre-apoptotic proteins Bax/Bak, caspase 8, BAP31 cleavage, and membrane translocation of CRT/endoplasmic reticulum-resident protein 57 were seen. Idebenone protected against alcohol-mediated liver injury. CONCLUSIONS Alcohol induces p46Shc-dependent activation of pre-apoptotic pathways and translocation of CRT to the membrane, where it acts as a damage-associated molecular pattern, instigating immunogenicity. Shc inhibition could be a novel treatment strategy in AH.
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Affiliation(s)
- Yuan Li
- Gastroenterology and Hepatology, Stanford University, VA Palo Alto, Palo Alto, California
| | - Joy X Jiang
- Gastroenterology and Hepatology, University of California Davis Medical Center, Sacramento, California
| | - Weiguo Fan
- Gastroenterology and Hepatology, Stanford University, VA Palo Alto, Palo Alto, California
| | - Sarah R Fish
- Gastroenterology and Hepatology, University of California Davis Medical Center, Sacramento, California
| | - Suvarthi Das
- Gastroenterology and Hepatology, Stanford University, VA Palo Alto, Palo Alto, California
| | - Parul Gupta
- Gastroenterology and Hepatology, Stanford University, VA Palo Alto, Palo Alto, California
| | - Gergely Mozes
- Gastroenterology and Hepatology, Stanford University, VA Palo Alto, Palo Alto, California
| | - Lorand Vancza
- Gastroenterology and Hepatology, Stanford University, VA Palo Alto, Palo Alto, California
| | - Sutapa Sarkar
- Gastroenterology and Hepatology, Stanford University, VA Palo Alto, Palo Alto, California
| | - Koshi Kunimoto
- Gastroenterology and Hepatology, Stanford University, VA Palo Alto, Palo Alto, California
| | - Dongning Chen
- Gastroenterology and Hepatology, Stanford University, VA Palo Alto, Palo Alto, California
| | - Hyesuk Park
- Gastroenterology and Hepatology, Stanford University, VA Palo Alto, Palo Alto, California
| | - Dahn Clemens
- Internal Medicine, University of Nebraska Medical Center, Omaha, Nebraska
| | - Alexey Tomilov
- Molecular Biosciences, School of Veterinary Medicine, University of California Davis, Davis, California
| | - Gino Cortopassi
- Molecular Biosciences, School of Veterinary Medicine, University of California Davis, Davis, California
| | - Natalie J Török
- Gastroenterology and Hepatology, Stanford University, VA Palo Alto, Palo Alto, California.
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23
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Alshehade S, Alshawsh MA, Murugaiyah V, Asif M, Alshehade O, Almoustafa H, Al Zarzour RH. The role of protein kinases as key drivers of metabolic dysfunction-associated fatty liver disease progression: New insights and future directions. Life Sci 2022; 305:120732. [PMID: 35760093 DOI: 10.1016/j.lfs.2022.120732] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/10/2022] [Revised: 06/08/2022] [Accepted: 06/21/2022] [Indexed: 02/07/2023]
Abstract
Metabolic dysfunction-associated fatty liver disease (MAFLD), proposed in 2020 is a novel term for non-alcoholic fatty liver disease (NAFLD) which was coined for the first time in 1980. It is a leading cause of the most chronic liver disease and hepatic failure all over the world, and unfortunately, with no licensed drugs for treatment yet. The progress of the disease is driven by the triggered inflammatory process, oxidative stress, and insulin resistance in many pathways, starting with simple hepatic steatosis to non-alcoholic steatohepatitis, fibrosis, cirrhosis, and liver cancer. Protein kinases (PKs), such as MAPK, ErbB, PKC, PI3K/Akt, and mTOR, govern most of the pathological pathways by acting on various downstream key points in MAFLD and regulating both hepatic gluco- lipo-neogenesis and inflammation. Therefore, modulating the function of those potential protein kinases that are effectively involved in MAFLD might be a promising therapeutic approach for tackling this disease. In the current review, we have discussed the key role of protein kinases in the pathogenesis of MAFLD and performed a protein-protein interaction (PPI) network among the main proteins of each kinase pathway with MAFLD-related proteins to predict the most likely targets of the PKs in MAFLD. Moreover, we have reported the experimental, pre-clinical, and clinical data for the most recent investigated molecules that are activating p38-MAPK and AMPK proteins and inhibiting the other PKs to improve MAFLD condition by regulating oxidation and inflammation signalling.
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Affiliation(s)
- Salah Alshehade
- Department of Pharmacology, School of Pharmaceutical Sciences, Universiti Sains Malaysia, 11800 Penang, Malaysia; Department of Pharmacology, Faculty of Medicine, Universiti Malaya, 50603 Kuala Lumpur, Malaysia
| | | | - Vikneswaran Murugaiyah
- Department of Pharmacology, School of Pharmaceutical Sciences, Universiti Sains Malaysia, 11800 Penang, Malaysia
| | - Muhammad Asif
- Department of Pharmacology, Faculty of Pharmacy, The Islamia University of Bahawalpur, 63100, Punjab, Pakistan
| | - Omayma Alshehade
- Department of Paediatrics, Faculty of Medicine, Damascus University, Damascus, Syria
| | - Hassan Almoustafa
- Department of Pharmacology, Faculty of Medicine, Universiti Malaya, 50603 Kuala Lumpur, Malaysia
| | - Raghdaa Hamdan Al Zarzour
- Department of Pharmacology, School of Pharmaceutical Sciences, Universiti Sains Malaysia, 11800 Penang, Malaysia; Department of Pharmacology, Faculty of Pharmacy, Arab International University, Damascus, Syria.
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24
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Xu X, Poulsen KL, Wu L, Liu S, Miyata T, Song Q, Wei Q, Zhao C, Lin C, Yang J. Targeted therapeutics and novel signaling pathways in non-alcohol-associated fatty liver/steatohepatitis (NAFL/NASH). Signal Transduct Target Ther 2022; 7:287. [PMID: 35963848 PMCID: PMC9376100 DOI: 10.1038/s41392-022-01119-3] [Citation(s) in RCA: 178] [Impact Index Per Article: 59.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/12/2022] [Revised: 06/15/2022] [Accepted: 07/08/2022] [Indexed: 11/24/2022] Open
Abstract
Non-alcohol-associated fatty liver/steatohepatitis (NAFL/NASH) has become the leading cause of liver disease worldwide. NASH, an advanced form of NAFL, can be progressive and more susceptible to developing cirrhosis and hepatocellular carcinoma. Currently, lifestyle interventions are the most essential and effective strategies for preventing and controlling NAFL without the development of fibrosis. While there are still limited appropriate drugs specifically to treat NAFL/NASH, growing progress is being seen in elucidating the pathogenesis and identifying therapeutic targets. In this review, we discussed recent developments in etiology and prospective therapeutic targets, as well as pharmacological candidates in pre/clinical trials and patents, with a focus on diabetes, hepatic lipid metabolism, inflammation, and fibrosis. Importantly, growing evidence elucidates that the disruption of the gut-liver axis and microbe-derived metabolites drive the pathogenesis of NAFL/NASH. Extracellular vesicles (EVs) act as a signaling mediator, resulting in lipid accumulation, macrophage and hepatic stellate cell activation, further promoting inflammation and liver fibrosis progression during the development of NAFL/NASH. Targeting gut microbiota or EVs may serve as new strategies for the treatment of NAFL/NASH. Finally, other mechanisms, such as cell therapy and genetic approaches, also have enormous therapeutic potential. Incorporating drugs with different mechanisms and personalized medicine may improve the efficacy to better benefit patients with NAFL/NASH.
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Affiliation(s)
- Xiaohan Xu
- School of Medicine and Pharmacy, Ocean University of China, Qingdao, China
| | - Kyle L Poulsen
- Department of Anesthesiology, McGovern Medical School, University of Texas Health Science Center, Houston, TX, USA
| | - Lijuan Wu
- School of Medicine and Pharmacy, Ocean University of China, Qingdao, China
- Innovation Center of Marine Drug Screening & Evaluation, Qingdao National Laboratory for Marine Science and Technology, Qingdao, China
| | - Shan Liu
- Innovation Center of Marine Drug Screening & Evaluation, Qingdao National Laboratory for Marine Science and Technology, Qingdao, China
| | - Tatsunori Miyata
- Department of Gastroenterological Surgery, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan
| | - Qiaoling Song
- Innovation Center of Marine Drug Screening & Evaluation, Qingdao National Laboratory for Marine Science and Technology, Qingdao, China
| | - Qingda Wei
- School of Medicine, Zhengzhou University, Zhengzhou, China
| | - Chenyang Zhao
- School of Medicine and Pharmacy, Ocean University of China, Qingdao, China
- Innovation Center of Marine Drug Screening & Evaluation, Qingdao National Laboratory for Marine Science and Technology, Qingdao, China
| | - Chunhua Lin
- Department of Urology, The Affiliated Yantai Yuhuangding Hospital of Qingdao University, Yantai, China
| | - Jinbo Yang
- School of Medicine and Pharmacy, Ocean University of China, Qingdao, China.
- Innovation Center of Marine Drug Screening & Evaluation, Qingdao National Laboratory for Marine Science and Technology, Qingdao, China.
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25
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Yamaguchi T, Yoshida K, Murata M, Suwa K, Tsuneyama K, Matsuzaki K, Naganuma M. Smad3 Phospho-Isoform Signaling in Nonalcoholic Steatohepatitis. Int J Mol Sci 2022; 23:ijms23116270. [PMID: 35682957 PMCID: PMC9181097 DOI: 10.3390/ijms23116270] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/18/2022] [Revised: 05/28/2022] [Accepted: 05/29/2022] [Indexed: 02/07/2023] Open
Abstract
Nonalcoholic fatty liver disease (NAFLD) is characterized by hepatic steatosis with insulin resistance, oxidative stress, lipotoxicity, adipokine secretion by fat cells, endotoxins (lipopolysaccharides) released by gut microbiota, and endoplasmic reticulum stress. Together, these factors promote NAFLD progression from steatosis to nonalcoholic steatohepatitis (NASH), fibrosis, and eventually end-stage liver diseases in a proportion of cases. Hepatic fibrosis and carcinogenesis often progress together, sharing inflammatory pathways. However, NASH can lead to hepatocarcinogenesis with minimal inflammation or fibrosis. In such instances, insulin resistance, oxidative stress, and lipotoxicity can directly lead to liver carcinogenesis through genetic and epigenetic alterations. Transforming growth factor (TGF)-β signaling is implicated in hepatic fibrogenesis and carcinogenesis. TGF-β type I receptor (TβRI) and activated-Ras/c-Jun-N-terminal kinase (JNK) differentially phosphorylate the mediator Smad3 to create two phospho-isoforms: C-terminally phosphorylated Smad3 (pSmad3C) and linker-phosphorylated Smad3 (pSmad3L). TβRI/pSmad3C signaling terminates cell proliferation, while constitutive Ras activation and JNK-mediated pSmad3L promote hepatocyte proliferation and carcinogenesis. The pSmad3L signaling pathway also antagonizes cytostatic pSmad3C signaling. This review addresses TGF-β/Smad signaling in hepatic carcinogenesis complicating NASH. We also discuss Smad phospho-isoforms as biomarkers predicting HCC in NASH patients with or without cirrhosis.
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Affiliation(s)
- Takashi Yamaguchi
- Department of Gastroenterology and Hepatology, Kansai Medical University, 2-5-1 Shin-machi, Hirakata, Osaka 573-1010, Japan; (K.Y.); (M.M.); (K.S.); (K.M.); (M.N.)
- Correspondence: ; Tel.: +81-72-804-0101; Fax: +81-72-804-2524
| | - Katsunori Yoshida
- Department of Gastroenterology and Hepatology, Kansai Medical University, 2-5-1 Shin-machi, Hirakata, Osaka 573-1010, Japan; (K.Y.); (M.M.); (K.S.); (K.M.); (M.N.)
| | - Miki Murata
- Department of Gastroenterology and Hepatology, Kansai Medical University, 2-5-1 Shin-machi, Hirakata, Osaka 573-1010, Japan; (K.Y.); (M.M.); (K.S.); (K.M.); (M.N.)
| | - Kanehiko Suwa
- Department of Gastroenterology and Hepatology, Kansai Medical University, 2-5-1 Shin-machi, Hirakata, Osaka 573-1010, Japan; (K.Y.); (M.M.); (K.S.); (K.M.); (M.N.)
| | - Koichi Tsuneyama
- Department of Pathology & Laboratory Medicine, Institute of Biomedical Sciences, Tokushima University Graduate School, 3-18-15 Kuramoto, Tokushima 770-8503, Japan;
| | - Koichi Matsuzaki
- Department of Gastroenterology and Hepatology, Kansai Medical University, 2-5-1 Shin-machi, Hirakata, Osaka 573-1010, Japan; (K.Y.); (M.M.); (K.S.); (K.M.); (M.N.)
| | - Makoto Naganuma
- Department of Gastroenterology and Hepatology, Kansai Medical University, 2-5-1 Shin-machi, Hirakata, Osaka 573-1010, Japan; (K.Y.); (M.M.); (K.S.); (K.M.); (M.N.)
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26
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Du Y, Zhang W, Qiu H, Xiao C, Shi J, Reid LM, He Z. Mouse Models of Liver Parenchyma Injuries and Regeneration. Front Cell Dev Biol 2022; 10:903740. [PMID: 35721478 PMCID: PMC9198899 DOI: 10.3389/fcell.2022.903740] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/24/2022] [Accepted: 04/11/2022] [Indexed: 12/11/2022] Open
Abstract
Mice have genetic and physiological similarities with humans and a well-characterized genetic background that is easy to manipulate. Murine models have become the most favored, robust mammalian systems for experimental analyses of biological processes and disease conditions due to their low cost, rapid reproduction, a wealth of mouse strains with defined genetic conditions (both native ones as well as ones established experimentally), and high reproducibility with respect to that which can be done in experimental studies. In this review, we focus on murine models for liver, an organ with renown regenerative capacity and the organ most central to systemic, complex metabolic and physiological functions for mammalian hosts. Establishment of murine models has been achieved for all aspects of studies of normal liver, liver diseases, liver injuries, and regenerative repair mechanisms. We summarize key information on current mouse systems that partially model facets of clinical scenarios, particularly those associated with drug-induced acute or chronic liver injuries, dietary related, non-alcoholic liver disease (NAFLD), hepatitis virus infectious chronic liver diseases, and autoimmune hepatitis (AIH). In addition, we also include mouse models that are suitable for studying liver cancers (e.g., hepatocellular carcinomas), the aging process (senescence, apoptosis), and various types of liver injuries and regenerative processes associated with them.
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Affiliation(s)
- Yuan Du
- Department of General Surgery, Ji’an Hospital, Shanghai East Hospital, School of Medicine, Tongji University, Ji’an, China
- Institute for Regenerative Medicine, Shanghai East Hospital, School of Life Sciences and Technology, Tongji University, Shanghai, China
- The First Affiliated Hospital of Nanchang University, Nanchang, China
| | - Wencheng Zhang
- Institute for Regenerative Medicine, Shanghai East Hospital, School of Life Sciences and Technology, Tongji University, Shanghai, China
- Shanghai Institute of Stem Cell Research and Clinical Translation, Shanghai, China
- Shanghai Engineering Research Center of Stem Cells Translational Medicine, Shanghai, China
| | - Hua Qiu
- Department of General Surgery, Ji’an Hospital, Shanghai East Hospital, School of Medicine, Tongji University, Ji’an, China
- Institute for Regenerative Medicine, Shanghai East Hospital, School of Life Sciences and Technology, Tongji University, Shanghai, China
- The First Affiliated Hospital of Nanchang University, Nanchang, China
| | - Canjun Xiao
- Department of General Surgery, Ji’an Hospital, Shanghai East Hospital, School of Medicine, Tongji University, Ji’an, China
| | - Jun Shi
- Department of General Surgery, Ji’an Hospital, Shanghai East Hospital, School of Medicine, Tongji University, Ji’an, China
- The First Affiliated Hospital of Nanchang University, Nanchang, China
- *Correspondence: Zhiying He, ; Lola M. Reid, , ; Jun Shi,
| | - Lola M. Reid
- Departments of Cell Biology and Physiology, Program in Molecular Biology and Biotechnology, UNC School of Medicine, Chapel Hill, NC, United States
- *Correspondence: Zhiying He, ; Lola M. Reid, , ; Jun Shi,
| | - Zhiying He
- Department of General Surgery, Ji’an Hospital, Shanghai East Hospital, School of Medicine, Tongji University, Ji’an, China
- Institute for Regenerative Medicine, Shanghai East Hospital, School of Life Sciences and Technology, Tongji University, Shanghai, China
- Shanghai Institute of Stem Cell Research and Clinical Translation, Shanghai, China
- Shanghai Engineering Research Center of Stem Cells Translational Medicine, Shanghai, China
- *Correspondence: Zhiying He, ; Lola M. Reid, , ; Jun Shi,
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Smati S, Polizzi A, Fougerat A, Ellero-Simatos S, Blum Y, Lippi Y, Régnier M, Laroyenne A, Huillet M, Arif M, Zhang C, Lasserre F, Marrot A, Al Saati T, Wan J, Sommer C, Naylies C, Batut A, Lukowicz C, Fougeray T, Tramunt B, Dubot P, Smith L, Bertrand-Michel J, Hennuyer N, Pradere JP, Staels B, Burcelin R, Lenfant F, Arnal JF, Levade T, Gamet-Payrastre L, Lagarrigue S, Loiseau N, Lotersztajn S, Postic C, Wahli W, Bureau C, Guillaume M, Mardinoglu A, Montagner A, Gourdy P, Guillou H. Integrative study of diet-induced mouse models of NAFLD identifies PPARα as a sexually dimorphic drug target. Gut 2022; 71:807-821. [PMID: 33903148 DOI: 10.1136/gutjnl-2020-323323] [Citation(s) in RCA: 40] [Impact Index Per Article: 13.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/10/2020] [Revised: 03/28/2021] [Accepted: 04/09/2021] [Indexed: 12/20/2022]
Abstract
OBJECTIVE We evaluated the influence of sex on the pathophysiology of non-alcoholic fatty liver disease (NAFLD). We investigated diet-induced phenotypic responses to define sex-specific regulation between healthy liver and NAFLD to identify influential pathways in different preclinical murine models and their relevance in humans. DESIGN Different models of diet-induced NAFLD (high-fat diet, choline-deficient high-fat diet, Western diet or Western diet supplemented with fructose and glucose in drinking water) were compared with a control diet in male and female mice. We performed metabolic phenotyping, including plasma biochemistry and liver histology, untargeted large-scale approaches (liver metabolome, lipidome and transcriptome), gene expression profiling and network analysis to identify sex-specific pathways in the mouse liver. RESULTS The different diets induced sex-specific responses that illustrated an increased susceptibility to NAFLD in male mice. The most severe lipid accumulation and inflammation/fibrosis occurred in males receiving the high-fat diet and Western diet, respectively. Sex-biased hepatic gene signatures were identified for these different dietary challenges. The peroxisome proliferator-activated receptor α (PPARα) co-expression network was identified as sexually dimorphic, and in vivo experiments in mice demonstrated that hepatocyte PPARα determines a sex-specific response to fasting and treatment with pemafibrate, a selective PPARα agonist. Liver molecular signatures in humans also provided evidence of sexually dimorphic gene expression profiles and the sex-specific co-expression network for PPARα. CONCLUSIONS These findings underscore the sex specificity of NAFLD pathophysiology in preclinical studies and identify PPARα as a pivotal, sexually dimorphic, pharmacological target. TRIAL REGISTRATION NUMBER NCT02390232.
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Affiliation(s)
- Sarra Smati
- Toxalim (Research Center in Food Toxicology), INRAE, ENVT, INP- PURPAN, UMR 1331, UPS, Université de Toulouse, Toulouse, France.,Institut des Maladies Métaboliques et Cardiovasculaires (I2MC), UMR1297, INSERM/UPS, Université de Toulouse, Toulouse, France
| | - Arnaud Polizzi
- Toxalim (Research Center in Food Toxicology), INRAE, ENVT, INP- PURPAN, UMR 1331, UPS, Université de Toulouse, Toulouse, France
| | - Anne Fougerat
- Toxalim (Research Center in Food Toxicology), INRAE, ENVT, INP- PURPAN, UMR 1331, UPS, Université de Toulouse, Toulouse, France
| | - Sandrine Ellero-Simatos
- Toxalim (Research Center in Food Toxicology), INRAE, ENVT, INP- PURPAN, UMR 1331, UPS, Université de Toulouse, Toulouse, France
| | - Yuna Blum
- CIT, Ligue Nationale Contre Le Cancer, Paris, France.,IGDR UMR 6290, CNRS, Université de Rennes 1, Rennes, France
| | - Yannick Lippi
- Toxalim (Research Center in Food Toxicology), INRAE, ENVT, INP- PURPAN, UMR 1331, UPS, Université de Toulouse, Toulouse, France
| | - Marion Régnier
- Toxalim (Research Center in Food Toxicology), INRAE, ENVT, INP- PURPAN, UMR 1331, UPS, Université de Toulouse, Toulouse, France
| | - Alexia Laroyenne
- Toxalim (Research Center in Food Toxicology), INRAE, ENVT, INP- PURPAN, UMR 1331, UPS, Université de Toulouse, Toulouse, France
| | - Marine Huillet
- Toxalim (Research Center in Food Toxicology), INRAE, ENVT, INP- PURPAN, UMR 1331, UPS, Université de Toulouse, Toulouse, France
| | - Muhammad Arif
- Science for Life Laboratory, KTH-Royal Institute of Technology, Solna, Sweden
| | - Cheng Zhang
- Science for Life Laboratory, KTH-Royal Institute of Technology, Solna, Sweden
| | - Frederic Lasserre
- Toxalim (Research Center in Food Toxicology), INRAE, ENVT, INP- PURPAN, UMR 1331, UPS, Université de Toulouse, Toulouse, France
| | - Alain Marrot
- Toxalim (Research Center in Food Toxicology), INRAE, ENVT, INP- PURPAN, UMR 1331, UPS, Université de Toulouse, Toulouse, France
| | - Talal Al Saati
- Experimental Histopathology Department, INSERM US006-CREFRE, University Hospital of Toulouse, Toulouse, France
| | - JingHong Wan
- INSERM-UMR1149, Centre de Recherche sur l'Inflammation, Paris, France.,Sorbonne Paris Cité, Laboratoire d'Excellence Inflamex, Faculté de Médecine, Site Xavier Bichat, Université Paris Diderot, Paris, France
| | - Caroline Sommer
- Toxalim (Research Center in Food Toxicology), INRAE, ENVT, INP- PURPAN, UMR 1331, UPS, Université de Toulouse, Toulouse, France
| | - Claire Naylies
- Toxalim (Research Center in Food Toxicology), INRAE, ENVT, INP- PURPAN, UMR 1331, UPS, Université de Toulouse, Toulouse, France
| | - Aurelie Batut
- Institut des Maladies Métaboliques et Cardiovasculaires (I2MC), UMR1297, INSERM/UPS, Université de Toulouse, Toulouse, France
| | - Celine Lukowicz
- Toxalim (Research Center in Food Toxicology), INRAE, ENVT, INP- PURPAN, UMR 1331, UPS, Université de Toulouse, Toulouse, France
| | - Tiffany Fougeray
- Toxalim (Research Center in Food Toxicology), INRAE, ENVT, INP- PURPAN, UMR 1331, UPS, Université de Toulouse, Toulouse, France
| | - Blandine Tramunt
- Institut des Maladies Métaboliques et Cardiovasculaires (I2MC), UMR1297, INSERM/UPS, Université de Toulouse, Toulouse, France
| | - Patricia Dubot
- Laboratoire de Biochimie Métabolique, CHU Toulouse, Toulouse, France.,INSERM U1037, CRCT, Université Paul Sabatier, Toulouse, France
| | - Lorraine Smith
- Toxalim (Research Center in Food Toxicology), INRAE, ENVT, INP- PURPAN, UMR 1331, UPS, Université de Toulouse, Toulouse, France
| | - Justine Bertrand-Michel
- Institut des Maladies Métaboliques et Cardiovasculaires (I2MC), UMR1297, INSERM/UPS, Université de Toulouse, Toulouse, France
| | - Nathalie Hennuyer
- Univ. Lille, INSERM, CHU Lille, Institut Pasteur de Lille, U1011-EGID, F-59000, Lille, France
| | - Jean-Philippe Pradere
- Institut des Maladies Métaboliques et Cardiovasculaires (I2MC), UMR1297, INSERM/UPS, Université de Toulouse, Toulouse, France
| | - Bart Staels
- Univ. Lille, INSERM, CHU Lille, Institut Pasteur de Lille, U1011-EGID, F-59000, Lille, France
| | - Remy Burcelin
- Institut des Maladies Métaboliques et Cardiovasculaires (I2MC), UMR1297, INSERM/UPS, Université de Toulouse, Toulouse, France
| | - Françoise Lenfant
- Institut des Maladies Métaboliques et Cardiovasculaires (I2MC), UMR1297, INSERM/UPS, Université de Toulouse, Toulouse, France
| | - Jean-François Arnal
- Institut des Maladies Métaboliques et Cardiovasculaires (I2MC), UMR1297, INSERM/UPS, Université de Toulouse, Toulouse, France
| | - Thierry Levade
- Laboratoire de Biochimie Métabolique, CHU Toulouse, Toulouse, France.,INSERM U1037, CRCT, Université Paul Sabatier, Toulouse, France
| | - Laurence Gamet-Payrastre
- Toxalim (Research Center in Food Toxicology), INRAE, ENVT, INP- PURPAN, UMR 1331, UPS, Université de Toulouse, Toulouse, France
| | | | - Nicolas Loiseau
- Toxalim (Research Center in Food Toxicology), INRAE, ENVT, INP- PURPAN, UMR 1331, UPS, Université de Toulouse, Toulouse, France
| | - Sophie Lotersztajn
- INSERM-UMR1149, Centre de Recherche sur l'Inflammation, Paris, France.,Sorbonne Paris Cité, Laboratoire d'Excellence Inflamex, Faculté de Médecine, Site Xavier Bichat, Université Paris Diderot, Paris, France
| | - Catherine Postic
- Université de Paris, Institut Cochin, CNRS, INSERM, Paris, France
| | - Walter Wahli
- Toxalim (Research Center in Food Toxicology), INRAE, ENVT, INP- PURPAN, UMR 1331, UPS, Université de Toulouse, Toulouse, France.,Lee Kong Chian School of Medicine, Nanyang Technological University, Singapore.,Center for Integrative Genomics, University of Lausanne, Le Génopode, Lausanne, Switzerland
| | - Christophe Bureau
- Hepatology Unit, Rangueil Hospital Toulouse, Paul Sabatier University Toulouse 3, Toulouse, France
| | - Maeva Guillaume
- Hepatology Unit, Rangueil Hospital Toulouse, Paul Sabatier University Toulouse 3, Toulouse, France
| | - Adil Mardinoglu
- Science for Life Laboratory, KTH-Royal Institute of Technology, Solna, Sweden.,Centre for Host-Microbiome Interactions, Faculty of Dentistry, Oral & Craniofacial Sciences, King's College London, London, UK
| | - Alexandra Montagner
- Institut des Maladies Métaboliques et Cardiovasculaires (I2MC), UMR1297, INSERM/UPS, Université de Toulouse, Toulouse, France
| | - Pierre Gourdy
- Institut des Maladies Métaboliques et Cardiovasculaires (I2MC), UMR1297, INSERM/UPS, Université de Toulouse, Toulouse, France .,Endocrinology-Diabetology-Nutrition Department, Toulouse University Hospital, Toulouse, France
| | - Hervé Guillou
- Toxalim (Research Center in Food Toxicology), INRAE, ENVT, INP- PURPAN, UMR 1331, UPS, Université de Toulouse, Toulouse, France
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28
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Karkucinska-Wieckowska A, Simoes ICM, Kalinowski P, Lebiedzinska-Arciszewska M, Zieniewicz K, Milkiewicz P, Górska-Ponikowska M, Pinton P, Malik AN, Krawczyk M, Oliveira PJ, Wieckowski MR. Mitochondria, oxidative stress and nonalcoholic fatty liver disease: A complex relationship. Eur J Clin Invest 2022; 52:e13622. [PMID: 34050922 DOI: 10.1111/eci.13622] [Citation(s) in RCA: 70] [Impact Index Per Article: 23.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/24/2021] [Revised: 05/19/2021] [Accepted: 05/22/2021] [Indexed: 02/06/2023]
Abstract
According to the 'multiple-hit' hypothesis, several factors can act simultaneously in nonalcoholic fatty liver disease (NAFLD) progression. Increased nitro-oxidative (nitroso-oxidative) stress may be considered one of the main contributors involved in the development and risk of NAFLD progression to nonalcoholic steatohepatitis (NASH) characterized by inflammation and fibrosis. Moreover, it has been repeatedly postulated that mitochondrial abnormalities are closely related to the development and progression of liver steatosis and NAFLD pathogenesis. However, it is difficult to determine with certainty whether mitochondrial dysfunction or oxidative stress are primary events or a simple consequence of NAFLD development. On the one hand, increasing lipid accumulation in hepatocytes could cause a wide range of effects from mild to severe mitochondrial damage with a negative impact on cell fate. This can start the cascade of events, including an increase of cellular reactive nitrogen species (RNS) and reactive oxygen species (ROS) production that promotes disease progression from simple steatosis to more severe NAFLD stages. On the other hand, progressing mitochondrial bioenergetic catastrophe and oxidative stress manifestation could be considered accompanying events in the vast spectrum of abnormalities observed during the transition from NAFL to NASH and cirrhosis. This review updates our current understanding of NAFLD pathogenesis and clarifies whether mitochondrial dysfunction and ROS/RNS are culprits or bystanders of NAFLD progression.
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Affiliation(s)
| | - Ines C M Simoes
- Laboratory of Mitochondrial Biology and Metabolism, Nencki Institute of Experimental Biology, Polish Academy of Sciences, Warsaw, Poland
| | - Piotr Kalinowski
- Department of General, Transplant and Liver Surgery, Medical University of Warsaw, Warsaw, Poland
| | - Magdalena Lebiedzinska-Arciszewska
- Laboratory of Mitochondrial Biology and Metabolism, Nencki Institute of Experimental Biology, Polish Academy of Sciences, Warsaw, Poland
| | - Krzysztof Zieniewicz
- Department of General, Transplant and Liver Surgery, Medical University of Warsaw, Warsaw, Poland
| | - Piotr Milkiewicz
- Liver and Internal Medicine Unit, Department of General, Transplant and Liver Surgery, Medical University of Warsaw, Warsaw, Poland
- Translational Medicine Group, Pomeranian Medical University, Szczecin, Poland
| | | | - Paolo Pinton
- Department of Medical Sciences, Laboratory for Technologies of Advanced Therapies, University of Ferrara, Ferrara, Italy
| | - Afshan N Malik
- Department of Diabetes, School of Life Course, Faculty of Life Sciences and Medicine, King's College London, London, UK
| | - Marcin Krawczyk
- Laboratory of Metabolic Liver Diseases, Department of General, Transplant and Liver Surgery, Centre for Preclinical Research, Medical University of Warsaw, Warsaw, Poland
- Department of Medicine II, Saarland University Medical Center, Saarland University, Homburg, Germany
| | - Paulo J Oliveira
- CNC - Center for Neuroscience and Cell Biology, University of Coimbra, CIBB - Centre for Innovative Biomedicine and Biotechnology, Coimbra, Portugal
| | - Mariusz R Wieckowski
- Laboratory of Mitochondrial Biology and Metabolism, Nencki Institute of Experimental Biology, Polish Academy of Sciences, Warsaw, Poland
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29
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Nagy MA, Hilgraf R, Mortensen DS, Elsner J, Norris S, Tikhe J, Yoon W, Paisner D, Delgado M, Erdman P, Haelewyn J, Khambatta G, Xu L, Romanow WJ, Condroski K, Bahmanyar S, McCarrick M, Benish B, Blease K, LeBrun L, Moghaddam MF, Apuy J, Canan SS, Bennett BL, Satoh Y. Discovery of the c-Jun N-Terminal Kinase Inhibitor CC-90001. J Med Chem 2021; 64:18193-18208. [PMID: 34894681 DOI: 10.1021/acs.jmedchem.1c01716] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
As a result of emerging biological data suggesting that within the c-Jun N-terminal kinase (JNK) family, JNK1 and not JNK2 or JNK3 may be primarily responsible for fibrosis pathology, we sought to identify JNK inhibitors with an increased JNK1 bias relative to our previous clinical compound tanzisertib (CC-930). This manuscript reports the synthesis and structure-activity relationship (SAR) studies for a novel series of JNK inhibitors demonstrating an increased JNK1 bias. SAR optimization on a series of 2,4-dialkylamino-pyrimidine-5-carboxamides resulted in the identification of compounds possessing low nanomolar JNK inhibitory potency, overall kinome selectivity, and the ability to inhibit cellular phosphorylation of the direct JNK substrate c-Jun. Optimization of physicochemical properties in this series resulted in compounds that demonstrated excellent systemic exposure following oral dosing, enabling in vivo efficacy studies and the selection of a candidate for clinical development, CC-90001, which is currently in clinical trials (Phase II) in patients with idiopathic pulmonary fibrosis (NCT03142191).
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Affiliation(s)
- Mark A Nagy
- Bristol Myers Squibb, 10300 Campus Point Drive, Suite 100, San Diego, California 92121, United States
| | - Robert Hilgraf
- Bristol Myers Squibb, 10300 Campus Point Drive, Suite 100, San Diego, California 92121, United States
| | - Deborah S Mortensen
- Bristol Myers Squibb, 10300 Campus Point Drive, Suite 100, San Diego, California 92121, United States
| | - Jan Elsner
- Bristol Myers Squibb, 10300 Campus Point Drive, Suite 100, San Diego, California 92121, United States
| | - Stephen Norris
- Bristol Myers Squibb, 10300 Campus Point Drive, Suite 100, San Diego, California 92121, United States
| | - Jayashree Tikhe
- Bristol Myers Squibb, 10300 Campus Point Drive, Suite 100, San Diego, California 92121, United States
| | - Won Yoon
- Bristol Myers Squibb, 10300 Campus Point Drive, Suite 100, San Diego, California 92121, United States
| | - David Paisner
- Bristol Myers Squibb, 10300 Campus Point Drive, Suite 100, San Diego, California 92121, United States
| | - Mercedes Delgado
- Bristol Myers Squibb, 10300 Campus Point Drive, Suite 100, San Diego, California 92121, United States
| | - Paul Erdman
- Bristol Myers Squibb, 10300 Campus Point Drive, Suite 100, San Diego, California 92121, United States
| | - Jason Haelewyn
- Bristol Myers Squibb, 10300 Campus Point Drive, Suite 100, San Diego, California 92121, United States
| | - Godrej Khambatta
- Bristol Myers Squibb, 10300 Campus Point Drive, Suite 100, San Diego, California 92121, United States
| | - Li Xu
- Bristol Myers Squibb, 10300 Campus Point Drive, Suite 100, San Diego, California 92121, United States
| | - William J Romanow
- Bristol Myers Squibb, 10300 Campus Point Drive, Suite 100, San Diego, California 92121, United States
| | - Kevin Condroski
- Bristol Myers Squibb, 10300 Campus Point Drive, Suite 100, San Diego, California 92121, United States
| | - Sogole Bahmanyar
- Bristol Myers Squibb, 10300 Campus Point Drive, Suite 100, San Diego, California 92121, United States
| | - Meg McCarrick
- Bristol Myers Squibb, 10300 Campus Point Drive, Suite 100, San Diego, California 92121, United States
| | - Brent Benish
- Bristol Myers Squibb, 10300 Campus Point Drive, Suite 100, San Diego, California 92121, United States
| | - Kate Blease
- Bristol Myers Squibb, 10300 Campus Point Drive, Suite 100, San Diego, California 92121, United States
| | - Laurie LeBrun
- Bristol Myers Squibb, 10300 Campus Point Drive, Suite 100, San Diego, California 92121, United States
| | - Mehran F Moghaddam
- Bristol Myers Squibb, 10300 Campus Point Drive, Suite 100, San Diego, California 92121, United States
| | - Julius Apuy
- Bristol Myers Squibb, 10300 Campus Point Drive, Suite 100, San Diego, California 92121, United States
| | - Stacie S Canan
- Bristol Myers Squibb, 10300 Campus Point Drive, Suite 100, San Diego, California 92121, United States
| | - Brydon L Bennett
- Bristol Myers Squibb, 10300 Campus Point Drive, Suite 100, San Diego, California 92121, United States
| | - Yoshitaka Satoh
- Bristol Myers Squibb, 10300 Campus Point Drive, Suite 100, San Diego, California 92121, United States
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30
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Song C, Lv W, Li Y, Nie P, Lu J, Geng Y, Heng Z, Song L. Alleviating the effect of quinoa and the underlying mechanism on hepatic steatosis in high-fat diet-fed rats. Nutr Metab (Lond) 2021; 18:106. [PMID: 34922572 PMCID: PMC8684231 DOI: 10.1186/s12986-021-00631-7] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/01/2021] [Accepted: 11/26/2021] [Indexed: 02/08/2023] Open
Abstract
Background Nonalcoholic fatty liver disease (NAFLD) is considered the hepatic component of metabolic syndrome and has attracted widespread attention due to its increased prevalence. Daily dietary management is an effective strategy for the prevention of NAFLD. Quinoa, a nutritious pseudocereal, is abundant in antioxidative bioactive phytochemicals. In the present study, the effects of different amounts of quinoa on the progression of NAFLD and the related molecular mechanism were investigated. Methods Male SD rats were simultaneously administered a high fat diet (HF) and different amounts of quinoa (equivalent to 100 g/day and 300 g/day of human intake, respectively). After 12 weeks of the intervention, hepatic TG (triglyceride) and TC (total cholesterol) as well as serum antioxidative parameters were determined, and hematoxylin–eosin staining (H&E) staining was used to evaluate hepatic steatosis. Differential metabolites in serum and hepatic tissue were identified using UPLC-QTOF-MSE. The mRNA expression profile was investigated using RNA-Seq and further verified using real-time polymerase chain reaction (RT-PCR). Results Low amounts of quinoa (equivalent to 100 g/d of human intake) effectively controlled the weight of rats fed a high-fat diet. In addition, quinoa effectively inhibited the increase in hepatic TG and TC levels, mitigated pathological injury, promoted the increase in SOD and GSH-Px activities, and decreased MDA levels. Nontarget metabolic profile analysis showed that quinoa regulated lipid metabolites in the circulation system and liver such as LysoPC and PC. RNA-Seq and RT-PCR verification revealed that a high amount of quinoa more effectively upregulated genes related to lipid metabolism [Apoa (apolipoprotein)5, Apoa4, Apoc2] and downregulated genes related to the immune response [lrf (interferon regulatory factor)5, Tlr6 (Toll-like receptor), Tlr10, Tlr11, Tlr12]. Conclusion Quinoa effectively prevented NAFLD by controlling body weight, mitigating oxidative stress, and regulating the lipid metabolic profile and the expression of genes related to lipid metabolism and the immune response. Supplementary Information The online version contains supplementary material available at 10.1186/s12986-021-00631-7.
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Affiliation(s)
- Chenwei Song
- School of Agriculture and Biology, Shanghai Jiao Tong University, Shanghai, 200240, China
| | - Wei Lv
- National Semi-Arid Agriculture Engineering Technology Research Center, Shijiazhuang, 050051, Hebei, China
| | - Yahui Li
- Center for Food Evaluation, State Administration for Market Regulation, Beijing, 100070, China
| | - Pan Nie
- School of Agriculture and Biology, Shanghai Jiao Tong University, Shanghai, 200240, China
| | - Jun Lu
- Shanghai Center for Plant Stress Biology, CAS Center for Excellence in Molecular Plant Sciences, Chinese Academy of Sciences, Shanghai, 201602, China
| | - Yanlou Geng
- National Semi-Arid Agriculture Engineering Technology Research Center, Shijiazhuang, 050051, Hebei, China.
| | - Zhang Heng
- Shanghai Center for Plant Stress Biology, CAS Center for Excellence in Molecular Plant Sciences, Chinese Academy of Sciences, Shanghai, 201602, China.
| | - Lihua Song
- School of Agriculture and Biology, Shanghai Jiao Tong University, Shanghai, 200240, China.
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31
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Bertran L, Portillo-Carrasquer M, Aguilar C, Porras JA, Riesco D, Martínez S, Vives M, Sabench F, Gonzalez E, Del Castillo D, Richart C, Auguet T. Deregulation of Secreted Frizzled-Related Protein 5 in Nonalcoholic Fatty Liver Disease Associated with Obesity. Int J Mol Sci 2021; 22:ijms22136895. [PMID: 34198988 PMCID: PMC8268103 DOI: 10.3390/ijms22136895] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/07/2021] [Revised: 06/23/2021] [Accepted: 06/25/2021] [Indexed: 12/12/2022] Open
Abstract
Secreted frizzled-related protein 5 (SFRP5), an antagonist of the noncanonical WNT pathway, has a controversial role in liver disease. The aim of this study was to analyze the role of SFRP5 and the noncanonical WNT pathway in nonalcoholic fatty liver disease (NAFLD). Plasma SFRP5 levels were determined by ELISA in women with normal weight (NW; n = 20) and morbid obesity (MO; n = 69). Women with MO were subclassified according to hepatic histology into normal liver (NL; n = 28), NAFLD (n = 41) (simple steatosis (SS; n = 24), and nonalcoholic steatohepatitis (NASH; n = 17)). We used RT-qPCR to evaluate the hepatic mRNA expression of SFRP5, WNT5A, and JNK in women with MO. SFRP5 levels were lower in NW than in MO patients who underwent a very low-calorie diet before surgery. Hepatic SFRP5 mRNA expression was higher in SS than in NL or NASH; additionally, patients with hepatic inflammation or ballooning presented lower SFRP5 abundance. WNT5A and JNK expression was enhanced in NAFLD compared with NL. In conclusion, circulating SFRP5 levels depend on the diet, and hepatic SFRP5 seems to have a protective role in the first steps of NAFLD; however, SFRP5 could be deregulated in an advanced stage while WNT5A and JNK are activated, promoting liver damage.
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Affiliation(s)
- Laia Bertran
- Grup de Recerca GEMMAIR (AGAUR)-Medicina Aplicada (URV), Departament de Medicina i Cirurgia, University Rovira i Virgili (URV), Institutue d’Investigació Sanitària Pere Virgili (IISPV), 43007 Tarragona, Spain; (L.B.); (M.P.-C.); (C.A.); (C.R.)
| | - Marta Portillo-Carrasquer
- Grup de Recerca GEMMAIR (AGAUR)-Medicina Aplicada (URV), Departament de Medicina i Cirurgia, University Rovira i Virgili (URV), Institutue d’Investigació Sanitària Pere Virgili (IISPV), 43007 Tarragona, Spain; (L.B.); (M.P.-C.); (C.A.); (C.R.)
| | - Carmen Aguilar
- Grup de Recerca GEMMAIR (AGAUR)-Medicina Aplicada (URV), Departament de Medicina i Cirurgia, University Rovira i Virgili (URV), Institutue d’Investigació Sanitària Pere Virgili (IISPV), 43007 Tarragona, Spain; (L.B.); (M.P.-C.); (C.A.); (C.R.)
| | - José Antonio Porras
- Servei Medicina Interna, Hospital Universitari de Tarragona Joan XXIII, Mallafré Guasch, 4, 43007 Tarragona, Spain; (J.A.P.); (D.R.)
| | - David Riesco
- Servei Medicina Interna, Hospital Universitari de Tarragona Joan XXIII, Mallafré Guasch, 4, 43007 Tarragona, Spain; (J.A.P.); (D.R.)
| | - Salomé Martínez
- Servei Anatomia Patològica, Hospital Universitari de Tarragona Joan XXIII, Mallafré Guasch, 4, 43007 Tarragona, Spain;
| | - Margarita Vives
- Servei de Cirurgia, Hospital Sant Joan de Reus, Departament de Medicina i Cirurgia, Universitat Rovira i Virgili (URV), IISPV. Avinguda Doctor Josep Laporte, 2, 43204 Reus, Spain; (M.V.); (F.S.); (D.D.C.)
| | - Fàtima Sabench
- Servei de Cirurgia, Hospital Sant Joan de Reus, Departament de Medicina i Cirurgia, Universitat Rovira i Virgili (URV), IISPV. Avinguda Doctor Josep Laporte, 2, 43204 Reus, Spain; (M.V.); (F.S.); (D.D.C.)
| | - Eva Gonzalez
- Laboratori Clínic Institut Català de Salut (ICS), Hospital Universitari de Tarragona Joan XXIII, Mallafré Guasch, 4, 43007 Tarragona, Spain;
| | - Daniel Del Castillo
- Servei de Cirurgia, Hospital Sant Joan de Reus, Departament de Medicina i Cirurgia, Universitat Rovira i Virgili (URV), IISPV. Avinguda Doctor Josep Laporte, 2, 43204 Reus, Spain; (M.V.); (F.S.); (D.D.C.)
| | - Cristóbal Richart
- Grup de Recerca GEMMAIR (AGAUR)-Medicina Aplicada (URV), Departament de Medicina i Cirurgia, University Rovira i Virgili (URV), Institutue d’Investigació Sanitària Pere Virgili (IISPV), 43007 Tarragona, Spain; (L.B.); (M.P.-C.); (C.A.); (C.R.)
- Servei Medicina Interna, Hospital Universitari de Tarragona Joan XXIII, Mallafré Guasch, 4, 43007 Tarragona, Spain; (J.A.P.); (D.R.)
| | - Teresa Auguet
- Grup de Recerca GEMMAIR (AGAUR)-Medicina Aplicada (URV), Departament de Medicina i Cirurgia, University Rovira i Virgili (URV), Institutue d’Investigació Sanitària Pere Virgili (IISPV), 43007 Tarragona, Spain; (L.B.); (M.P.-C.); (C.A.); (C.R.)
- Servei Medicina Interna, Hospital Universitari de Tarragona Joan XXIII, Mallafré Guasch, 4, 43007 Tarragona, Spain; (J.A.P.); (D.R.)
- Correspondence: ; Tel.: +34-977-295-833
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Multi-target pharmacological mechanisms of Salvia miltiorrhiza against oral submucous fibrosis: A network pharmacology approach. Arch Oral Biol 2021; 126:105131. [PMID: 33894647 DOI: 10.1016/j.archoralbio.2021.105131] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/24/2021] [Revised: 04/11/2021] [Accepted: 04/15/2021] [Indexed: 02/08/2023]
Abstract
OBJECTIVES The herb Salvia miltiorrhiza is used to treat oral submucous fibrosis (OSF); however, the mechanism underlying its efficacy has not been elucidated. As such, a network pharmacology-based approach was applied to investigate the potential mechanisms of Salvia miltiorrhiza against OSF. MATERIALS AND METHODS Potential targets of Salvia miltiorrhiza were collected by Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform, Bioinformatics Analysis Tool for Molecular Mechanism of Traditional Chinese Medicine, and Swiss Target Prediction. Potential targets of OSF were collected from DisGeNET, GeneCards, and National Center for Biotechnology Information Gene database. Salvia miltiorrhiza against OSF targets protein-protein interaction and enrichment analyses network were constructed by Cytoscape and Metascape. RESULTS Twelve active ingredients from Salvia miltiorrhiza and 57 potential OSF-related targets were identified. The constructed network predicted seven potential key targets of Salvia miltiorrhiza for the treatment of OSF. Functional enrichment analysis showed that biological processes such as cellular response to drugs and pathways such as bladder cancer were mainly regulated by the Salvia miltiorrhiza active ingredient targets. Furthermore, the protein-protein interaction network demonstrated that the molecular complex detection components were mainly related to the ErbB signaling pathway, cancer pathways and IL-17 signaling. CONCLUSIONS A network approach was employed to document how Salvia miltiorrhiza active ingredients change various pathways against OSF. Salvia miltiorrhiza active ingredient targets against OSF involved CYP19A1, EGFR, PTPN11, ACHE, TERT, MAPK8 and PGR and were enriched in several signaling pathways.
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Zhou Y, Liu Z, Lynch EC, He L, Cheng H, Liu L, Li Z, Li J, Lawless L, Zhang KK, Xie L. Osr1 regulates hepatic inflammation and cell survival in the progression of non-alcoholic fatty liver disease. J Transl Med 2021; 101:477-489. [PMID: 33005011 PMCID: PMC7987871 DOI: 10.1038/s41374-020-00493-2] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/23/2020] [Revised: 09/12/2020] [Accepted: 09/13/2020] [Indexed: 02/07/2023] Open
Abstract
Odd-skipped related 1 (Osr1) is a novel tumor suppressor gene in several cancer cell lines. Non-alcoholic steatohepatitis (NASH) is considered as a high-risk factor for hepatocellular carcinoma (HCC). This study is aimed to investigate the novel role of Osr1 in promoting the progression of hepatic steatosis to NASH. Following 12 weeks of diethylnitrosamine (DEN) and high-fat diet (HFD), wildtype (WT) and Osr1 heterozygous (Osr1+/-) male mice were examined for liver injuries. Osr1+/- mice displayed worsen liver injury with higher serum alanine aminotransferase levels than the WT mice. The Osr1+/- mice also revealed early signs of collagen deposition with increased hepatic Tgfb and Fn1 expression. There was overactivation of both JNK and NF-κB signaling in the Osr1+/- liver, along with accumulation of F4/80+ cells and enhanced hepatic expression of Il-1b and Il-6. Moreover, the Osr1+/- liver displayed hyperphosphorylation of AKT/mTOR signaling, associated with overexpression of Bcl-2. In addition, Osr1+/- and WT mice displayed differences in the DNA methylome of the liver cells. Specifically, Osr1-responsible CpG islands of Ccl3 and Pcgf2, genes for inflammation and macrophage infiltration, were further identified. Taken together, Osr1 plays an important role in regulating cell inflammation and survival through multiple signaling pathways and DNA methylation modification for NAFLD progression.
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Affiliation(s)
- Yi Zhou
- Department of Nutrition, Texas A&M University, College Station, TX, 77843, USA
- Tongji Hospital, Huazhong University of Science and Technology, Wuhan, 430030, Hubei, China
| | - Zhimin Liu
- Department of Nutrition, Texas A&M University, College Station, TX, 77843, USA
- Department of Colorectal Surgery, The Sixth Affiliated Hospital of Sun Yat-sen University (Gastrointestinal and Anal Hospital of Sun Yat-sen Unversity), Guangzhou, 510655, China
| | - Ernest C Lynch
- Department of Nutrition, Texas A&M University, College Station, TX, 77843, USA
| | - Leya He
- Department of Nutrition, Texas A&M University, College Station, TX, 77843, USA
- Tongji Hospital, Huazhong University of Science and Technology, Wuhan, 430030, Hubei, China
| | - Henghui Cheng
- Department of Nutrition, Texas A&M University, College Station, TX, 77843, USA
- Tongji Hospital, Huazhong University of Science and Technology, Wuhan, 430030, Hubei, China
| | - Lin Liu
- Department of Nutrition, Texas A&M University, College Station, TX, 77843, USA
| | - Zhen Li
- Department of Nutrition, Texas A&M University, College Station, TX, 77843, USA
| | - Jiangyuan Li
- Department of Statistics, Texas A&M University, College Station, TX, 77843, USA
| | - Lauren Lawless
- Department of Nutrition, Texas A&M University, College Station, TX, 77843, USA
| | - Ke K Zhang
- Department of Nutrition, Texas A&M University, College Station, TX, 77843, USA
- Center for Epigenetics & Disease Prevention, Institute of Biosciences & Technology, College of Medicine, Texas A&M University, Houston, TX, USA
| | - Linglin Xie
- Department of Nutrition, Texas A&M University, College Station, TX, 77843, USA.
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Garg R, Kumariya S, Katekar R, Verma S, Goand UK, Gayen JR. JNK signaling pathway in metabolic disorders: An emerging therapeutic target. Eur J Pharmacol 2021; 901:174079. [PMID: 33812885 DOI: 10.1016/j.ejphar.2021.174079] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/14/2020] [Revised: 03/18/2021] [Accepted: 03/25/2021] [Indexed: 02/08/2023]
Abstract
Metabolic Syndrome is a multifactorial disease associated with increased risk of cardiovascular disorders, type 2 diabetes mellitus, fatty liver disease, etc. Various stress stimuli such as reactive oxygen species, endoplasmic reticulum stress, mitochondrial dysfunction, increased cytokines, or free fatty acids are known to aggravate progressive development of hyperglycemia and hyperlipidemia. Although the exact mechanism contributing to altered metabolism is unclear. Evidence suggests stress kinase role to be a crucial one in metabolic syndrome. Stress kinase, c-jun N-terminal kinase activation (JNK) is involved in various metabolic manifestations including obesity, insulin resistance, fatty liver disease as well as cardiometabolic disorders. It emerged as a foremost mediator in regulating metabolism in the liver, skeletal muscle, adipose tissue as well as pancreatic β cells. It has three isoforms each having a unique and tissue-specific role in altered metabolism. Current findings based on genetic manipulation or chemical inhibition studies identified JNK isoforms to play a central role in the regulation of whole-body metabolism, suggesting it to be a novel therapeutic target. Hence, it is imperative to elucidate its role in metabolic syndrome onset and progression. The purpose of this review is to elucidate in vitro and in vivo implications of JNK signaling along with the therapeutic strategy to inhibit specific isoform. Since metabolic syndrome is an array of diseases and complex pathway, carefully examining each tissue will be important for specific treatment strategies.
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Affiliation(s)
- Richa Garg
- Pharmaceutics & Pharmacokinetics, CSIR-Central Drug Research Institute, Jankipuram Extension, Lucknow, 226031, India; Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, 201002, India
| | - Sanjana Kumariya
- Pharmaceutics & Pharmacokinetics, CSIR-Central Drug Research Institute, Jankipuram Extension, Lucknow, 226031, India
| | - Roshan Katekar
- Pharmaceutics & Pharmacokinetics, CSIR-Central Drug Research Institute, Jankipuram Extension, Lucknow, 226031, India; Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, 201002, India
| | - Saurabh Verma
- Pharmaceutics & Pharmacokinetics, CSIR-Central Drug Research Institute, Jankipuram Extension, Lucknow, 226031, India; Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, 201002, India
| | - Umesh K Goand
- Pharmaceutics & Pharmacokinetics, CSIR-Central Drug Research Institute, Jankipuram Extension, Lucknow, 226031, India; Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, 201002, India
| | - Jiaur R Gayen
- Pharmaceutics & Pharmacokinetics, CSIR-Central Drug Research Institute, Jankipuram Extension, Lucknow, 226031, India; Pharmacology Division, CSIR-Central Drug Research Institute, Jankipuram Extension, Lucknow, 226031, India; Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, 201002, India.
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Kim JY, He F, Karin M. From Liver Fat to Cancer: Perils of the Western Diet. Cancers (Basel) 2021; 13:1095. [PMID: 33806428 PMCID: PMC7961422 DOI: 10.3390/cancers13051095] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/11/2021] [Revised: 02/27/2021] [Accepted: 02/28/2021] [Indexed: 02/06/2023] Open
Abstract
Hepatocellular carcinoma (HCC), the most common type of primary liver cancer provides the prototypical example of an obesity-related cancer. The obesity epidemic gave rise to an enormous increase in the incidence of non-alcoholic fatty liver disease (NAFLD), a condition that affects one third of American adults. In about 20% of these individuals, simple liver steatosis (hepatosteatosis) progresses to non-alcoholic steatohepatitis (NASH) characterized by chronic liver injury, inflammation, and fibrosis. In addition to liver failure, NASH greatly increases the risk of HCC. Here we discuss the metabolic processes that control the progression from NAFLD to NASH and from NASH to HCC, with a special emphasis on the role of free-non-esterified cholesterol in the process.
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Affiliation(s)
- Ju Youn Kim
- Laboratory of Gene Regulation and Signal Transduction, Departments of Pharmacology and Pathology, University of California San Diego, 9500 Gilman Drive, San Diego, CA 92093, USA;
| | - Feng He
- Academy of Integrative Medicine, Shanghai University of Traditional Chinese Medicine, 1200 Cailun Road, Shanghai 201203, China;
| | - Michael Karin
- Laboratory of Gene Regulation and Signal Transduction, Departments of Pharmacology and Pathology, University of California San Diego, 9500 Gilman Drive, San Diego, CA 92093, USA;
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Cicuéndez B, Ruiz-Garrido I, Mora A, Sabio G. Stress kinases in the development of liver steatosis and hepatocellular carcinoma. Mol Metab 2021; 50:101190. [PMID: 33588102 PMCID: PMC8324677 DOI: 10.1016/j.molmet.2021.101190] [Citation(s) in RCA: 31] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/12/2020] [Revised: 12/31/2020] [Accepted: 02/09/2021] [Indexed: 02/07/2023] Open
Abstract
Non-alcoholic fatty liver disease (NAFLD) is an important component of metabolic syndrome and one of the most prevalent liver diseases worldwide. This disorder is closely linked to hepatic insulin resistance, lipotoxicity, and inflammation. Although the mechanisms that cause steatosis and chronic liver injury in NAFLD remain unclear, a key component of this process is the activation of stress-activated kinases (SAPKs), including p38 and JNK in the liver and immune system. This review summarizes findings which indicate that the dysregulation of stress kinases plays a fundamental role in the development of steatosis and are important players in inducing liver fibrosis. To avoid the development of steatohepatitis and liver cancer, SAPK activity must be tightly regulated not only in the hepatocytes but also in other tissues, including cells of the immune system. Possible cellular mechanisms of SAPK actions are discussed.
Hepatic JNK triggers steatosis and insulin resistance, decreasing lipid oxidation and ketogenesis in HFD-fed mice. Decreased liver expression of p38α/β in HFD increases lipogenesis. Hepatic p38γ/δ drive insulin resistance and inhibit autophagy, which may lead to steatosis. Macrophage p38α/β promote cytokine production and M1 polarization, leading to lipid accumulation in hepatocytes. Myeloid p38γ/δ contribute to cytokine production and neutrophil migration, protecting against steatosis, diabetes and NAFLD. JNK1 and p38γ induce HCC while p38α blocks it. However, deletion of hepatic JNK1/2 induces cholangiocarcinoma. SAPK are potential therapeutic target for metabolic disorders, steatohepatitis and liver cancer.
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Affiliation(s)
- Beatriz Cicuéndez
- Centro Nacional de Investigaciones Cardiovasculares (CNIC), 28029 Madrid, Spain
| | - Irene Ruiz-Garrido
- Centro Nacional de Investigaciones Cardiovasculares (CNIC), 28029 Madrid, Spain
| | - Alfonso Mora
- Centro Nacional de Investigaciones Cardiovasculares (CNIC), 28029 Madrid, Spain.
| | - Guadalupe Sabio
- Centro Nacional de Investigaciones Cardiovasculares (CNIC), 28029 Madrid, Spain.
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Xie M, Chia RH, Li D, Teo FX, Krueger C, Sabapathy K. Functional interaction between macrophages and hepatocytes dictate the outcome of liver fibrosis. Life Sci Alliance 2021; 4:4/4/e202000803. [PMID: 33514653 PMCID: PMC7893818 DOI: 10.26508/lsa.202000803] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/03/2020] [Revised: 01/07/2021] [Accepted: 01/15/2021] [Indexed: 02/06/2023] Open
Abstract
Hepatocytes and liver-resident macrophages known as Kupffer cells (KCs) are key cell types involved in liver fibrosis. The transcription factor c-Jun plays a fundamental role in regulating hepatocyte and macrophage functions. We have examined c-Jun's role in the functional interaction of these cells during liver fibrosis induced by carbon tetrachloride. While hepatocyte-specific c-jun deletion led to increased fibrosis, the opposite outcome was observed when c-jun was deleted in both hepatocytes and KCs. Molecular analyses revealed compromised cytokine gene expression as the apical event related to the phenotype. Yet, purified hepatocytes from both mouse cohorts showed similar defects in cytokine gene expression. However, we noted increased macrophage infiltration in the absence of c-Jun in hepatocytes, which when chemically depleted, reversed the phenotype. Consistently, c-jun deletion in KCs alone also led to reduced fibrosis and cytokine gene expression. By contrast, c-jun deletion in hepatocytes and KCs did not affect the resolution phase after fibrotic injury. These data together demonstrate a pro-fibrogenic role for c-Jun in hepatocytes and KCs that functionally interact to regulate liver fibrosis.
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Affiliation(s)
- Min Xie
- Division of Cellular and Molecular Research, Humphrey Oei Institute of Cancer Research, National Cancer Centre Singapore, Singapore, Singapore
| | - Ren Hui Chia
- Division of Cellular and Molecular Research, Humphrey Oei Institute of Cancer Research, National Cancer Centre Singapore, Singapore, Singapore.,Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
| | - Dan Li
- Division of Cellular and Molecular Research, Humphrey Oei Institute of Cancer Research, National Cancer Centre Singapore, Singapore, Singapore
| | - Fanny Xueting Teo
- Division of Cellular and Molecular Research, Humphrey Oei Institute of Cancer Research, National Cancer Centre Singapore, Singapore, Singapore
| | - Christian Krueger
- Division of Cellular and Molecular Research, Humphrey Oei Institute of Cancer Research, National Cancer Centre Singapore, Singapore, Singapore
| | - Kanaga Sabapathy
- Division of Cellular and Molecular Research, Humphrey Oei Institute of Cancer Research, National Cancer Centre Singapore, Singapore, Singapore .,Cancer and Stem Cell Biology Program, Duke-NUS Medical School, Singapore, Singapore.,Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore.,Institute of Molecular and Cellular Biology, Singapore, Singapore
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Leng YR, Zhang MH, Luo JG, Zhang H. Pathogenesis of NASH and Promising Natural Products. Chin J Nat Med 2021; 19:12-27. [PMID: 33516448 DOI: 10.1016/s1875-5364(21)60002-x] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/23/2020] [Indexed: 02/08/2023]
Abstract
Nonalcoholic steatohepatitis (NASH) is a common clinical condition that can lead to advanced liver diseases. The mechanism of the diaease progression, which is lacking effective therapy, remains obsure. Therefore, there is a need to understand the pathogenic mechanisms responsible for disease development and progression in order to develop innovative therapies. To accomplish this goal, experimental animal models that recapitulate the human disease are necessary. Currently, an increasing number of studies have focused on natural constituents from medicinal plants which have been emerged as a new hope for NASH. This review summarized the pathogenesis of NASH, animal models commonly used, and the promising targets for therapeutics. We also reviewed the natural constituents as potential NASH therapeutic agents.
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Affiliation(s)
- Ying-Rong Leng
- State Key Laboratory of Natural Medicines and Jiangsu Key Laboratory of Bioactive Natural Product Research, School of Traditional Chinese Pharmacy, China Pharmaceutical University, Nanjing 210009, China
| | - Mei-Hui Zhang
- State Key Laboratory of Natural Medicines and Jiangsu Key Laboratory of Bioactive Natural Product Research, School of Traditional Chinese Pharmacy, China Pharmaceutical University, Nanjing 210009, China
| | - Jian-Guang Luo
- State Key Laboratory of Natural Medicines and Jiangsu Key Laboratory of Bioactive Natural Product Research, School of Traditional Chinese Pharmacy, China Pharmaceutical University, Nanjing 210009, China.
| | - Hao Zhang
- State Key Laboratory of Natural Medicines and Jiangsu Key Laboratory of Bioactive Natural Product Research, School of Traditional Chinese Pharmacy, China Pharmaceutical University, Nanjing 210009, China.
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Berumen J, Baglieri J, Kisseleva T, Mekeel K. Liver fibrosis: Pathophysiology and clinical implications. WIREs Mech Dis 2021; 13:e1499. [PMID: 32713091 PMCID: PMC9479486 DOI: 10.1002/wsbm.1499] [Citation(s) in RCA: 90] [Impact Index Per Article: 22.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/19/2019] [Revised: 04/30/2020] [Accepted: 05/21/2020] [Indexed: 02/06/2023]
Abstract
Liver fibrosis is a clinically significant finding that has major impacts on patient morbidity and mortality. The mechanism of fibrosis involves many different cellular pathways, but the major cell type involved appears to be hepatic stellate cells. Many liver diseases, including Hepatitis B, C, and fatty liver disease cause ongoing hepatocellular damage leading to liver fibrosis. No matter the cause of liver disease, liver-related mortality increases exponentially with increasing fibrosis. The progression to cirrhosis brings more dramatic mortality and higher incidence of hepatocellular carcinoma. Fibrosis can also affect outcomes following liver transplantation in adult and pediatric patients and require retransplantation. Drugs exist to treat Hepatitis B and C that reverse fibrosis in patients with those viral diseases, but there are currently no therapies to directly treat liver fibrosis. Several mouse models of chronic liver diseases have been successfully reversed using novel drug targets with current therapies focusing mostly on prevention of myofibroblast activation. Further research in these areas could lead to development of drugs to treat fibrosis, which will have invaluable impact on patient survival. This article is categorized under: Metabolic Diseases > Molecular and Cellular Physiology.
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Affiliation(s)
| | - Jacopo Baglieri
- Department of Surgery, University of California, San Diego
- Department of Medicine, University of California, San Diego
| | | | - Kristin Mekeel
- Department of Surgery, University of California, San Diego
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40
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Abstract
Nonalcoholic hepatitis (NASH) is the progressive inflammatory form of nonalcoholic fatty liver disease. Although the mechanisms of hepatic inflammation in NASH remain incompletely understood, emerging literature implicates the proinflammatory environment created by toxic lipid-induced hepatocyte injury, termed lipotoxicity. Interestingly, numerous NASH-promoting kinases in hepatocytes, immune cells, and adipocytes are activated by the lipotoxic insult associated with obesity. In the current review, we discuss recent advances in NASH-promoting kinases as disease mediators and therapeutic targets. The focus of the review is mainly on the mitogen-activated protein kinases including mixed lineage kinase 3, apoptosis signal-regulating kinase 1, c-Jun N-terminal kinase, and p38 MAPK; the endoplasmic reticulum (ER) stress kinases protein kinase RNA-like ER kinase and inositol-requiring protein-1α; as well as the Rho-associated protein kinase 1. We also discuss various pharmacological agents targeting these stress kinases in NASH that are under different phases of development.
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Affiliation(s)
- Samar H. Ibrahim
- Division of Gastroenterology & Hepatology in the Department of Pediatrics, Rochester, Minnesota.,Division of Gastroenterology & Hepatology in the Department of Medicine Mayo Clinic, Rochester, Minnesota
| | - Petra Hirsova
- Division of Gastroenterology & Hepatology in the Department of Medicine Mayo Clinic, Rochester, Minnesota
| | - Harmeet Malhi
- Division of Gastroenterology & Hepatology in the Department of Medicine Mayo Clinic, Rochester, Minnesota
| | - Gregory J. Gores
- Division of Gastroenterology & Hepatology in the Department of Medicine Mayo Clinic, Rochester, Minnesota
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41
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Ikeno Y, Ohara D, Takeuchi Y, Watanabe H, Kondoh G, Taura K, Uemoto S, Hirota K. Foxp3+ Regulatory T Cells Inhibit CCl 4-Induced Liver Inflammation and Fibrosis by Regulating Tissue Cellular Immunity. Front Immunol 2020; 11:584048. [PMID: 33178216 PMCID: PMC7593684 DOI: 10.3389/fimmu.2020.584048] [Citation(s) in RCA: 30] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/16/2020] [Accepted: 09/09/2020] [Indexed: 12/12/2022] Open
Abstract
Foxp3+ regulatory T (Treg) cells are pivotal in maintaining immunological self-tolerance and tissue homeostasis; however, it remains unclear how tissue Treg cells respond to liver injury and regulate chronic inflammation, which can cause liver fibrosis. We report here that hepatic Treg cells play a critical role in preventing liver pathology by suppressing inflammatory cellular immunity that can promote liver damage and fibrosis. Chronic liver inflammation induced by injections of carbon tetrachloride (CCl4) led to preferential expansion of hepatic Treg cells that prevented liver fibrosis. In contrast, depletion of Treg cells in the CCl4-induced liver fibrosis model exacerbated the severity of liver pathology. Treg depletion unleashed tissue cellular immunity and drove the activation and expansion of the pro-fibrotic IL-4-producing T helper 2 cells, as well as CCR2high Ly-6Chigh inflammatory monocytes/macrophages in the inflamed liver. Although Treg expression of amphiregulin plays a key role in tissue remodeling and repair in various inflammation models, amphiregulin from hepatic Treg cells, the largest producer among liver immune cells, was dispensable for maintaining liver homeostasis and preventing liver fibrosis during CCl4-induced chronic inflammation. Our results indicate that Treg cells control chronic liver inflammation and fibrosis by regulating the aberrant activation and functions of immune effector cells. Harnessing Treg functions, which effectively regulate tissue cellular immunity, may be a therapeutic strategy for preventing and treating liver fibrosis.
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Affiliation(s)
- Yoshinobu Ikeno
- Department of Hepatobiliary, Pancreas and Transplant Surgery, Graduate School of Medicine, Kyoto University, Kyoto, Japan
| | - Daiya Ohara
- Laboratory of Integrative Biological Science, Institute for Frontier Life and Medical Sciences, Kyoto University, Kyoto, Japan
| | - Yusuke Takeuchi
- Laboratory of Integrative Biological Science, Institute for Frontier Life and Medical Sciences, Kyoto University, Kyoto, Japan
| | - Hitomi Watanabe
- Laboratory of Integrative Biological Science, Institute for Frontier Life and Medical Sciences, Kyoto University, Kyoto, Japan
| | - Gen Kondoh
- Laboratory of Integrative Biological Science, Institute for Frontier Life and Medical Sciences, Kyoto University, Kyoto, Japan
| | - Kojiro Taura
- Department of Hepatobiliary, Pancreas and Transplant Surgery, Graduate School of Medicine, Kyoto University, Kyoto, Japan
| | - Shinji Uemoto
- Department of Hepatobiliary, Pancreas and Transplant Surgery, Graduate School of Medicine, Kyoto University, Kyoto, Japan
| | - Keiji Hirota
- Laboratory of Integrative Biological Science, Institute for Frontier Life and Medical Sciences, Kyoto University, Kyoto, Japan
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Lin YL, Li Y. Study on the hepatocellular carcinoma model with metastasis. Genes Dis 2020; 7:336-350. [PMID: 32884988 PMCID: PMC7452459 DOI: 10.1016/j.gendis.2019.12.008] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/11/2019] [Revised: 12/07/2019] [Accepted: 12/31/2019] [Indexed: 02/07/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is one of the most common causes of cancer-related death around the world due to advanced clinical stage at diagnosis, high incidence of recurrence and metastasis after surgical treatment. It is in urgent need to create appropriate animal models to explore the mechanism, patterns, risk factors, and therapeutic strategies of HCC metastasis and recurrence. However, most of the established models lack the phenotype of invasion and metastasis in patient, or have unstable phenotype. To establish HCC models with stable metastasis phenotype requires profound understanding in cancer metastasis biology and scientific methodology. Over the past 3 decades, HCC models with stable metastasis have been extensively studied. This paper reviewed the history and development of HCC animal models and cell models, focusing on the screening and maintaining of metastatic potential and phenotype. In-depth studies using these models vastly promote the understanding of cellular and molecular mechanisms and development of therapeutic strategies on HCC metastasis.
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Affiliation(s)
- Yu-Lin Lin
- Department of Peritoneal Cancer Surgery, Beijing Shijitan Hospital, Capital Medical University, Beijing, 100038, China
| | - Yan Li
- Department of Peritoneal Cancer Surgery, Beijing Shijitan Hospital, Capital Medical University, Beijing, 100038, China
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Guo X, Zhu B, Xu H, Li H, Jiang B, Wang Y, Zheng B, Glaser S, Alpini G, Wu C. Adoptive transfer of Pfkfb3-disrupted hematopoietic cells to wild-type mice exacerbates diet-induced hepatic steatosis and inflammation. LIVER RESEARCH 2020; 4:136-144. [PMID: 34336366 PMCID: PMC8320599 DOI: 10.1016/j.livres.2020.08.004] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
BACKGROUND AND OBJECTIVES Hepatic steatosis and inflammation are key characteristics of non-alcoholic fatty liver disease (NAFLD). However, whether and how hepatic steatosis and liver inflammation are differentially regulated remains to be elucidated. Considering that disruption of 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase 3 (Pfkfb3/iPfk2) dissociates fat deposition and inflammation, the present study examined a role for Pfkfb3/iPfk2 in hematopoietic cells in regulating hepatic steatosis and inflammation in mice. METHODS Pfkfb3-disrupted (Pfkfb3 +/-) mice and wild-type (WT) littermates were fed a high-fat diet (HFD) and examined for NAFLD phenotype. Also, bone marrow cells isolated from Pfkfb3 +/- mice and WT mice were differentiated into macrophages for analysis of macrophage activation status and for bone marrow transplantation (BMT) to generate chimeric (WT/BMT- Pfkfb3 +/-) mice in which Pfkfb3 was disrupted only in hematopoietic cells and control chimeric (WT/BMT-WT) mice. The latter were also fed an HFD and examined for NAFLD phenotype. In vitro, hepatocytes were co-cultured with bone marrow-derived macrophages and examined for hepatocyte fat deposition and proinflammatory responses. RESULTS After the feeding period, HFD-fed Pfkfb3 +/- mice displayed increased severity of liver inflammation in the absence of hepatic steatosis compared with HFD-fed WT mice. When inflammatory activation was analyzed, Pfkfb3 +/- macrophages revealed increased proinflammatory activation and decreased anti-proinflammatory activation. When NAFLD phenotype was analyzed in the chimeric mice, WT/BMT-Pfkfb3 +/- mice displayed increases in the severity of HFD-induced hepatic steatosis and inflammation compared with WT/BMT-WT mice. At the cellular level, hepatocytes co-cultured with Pfkfb3 +/- macrophages revealed increased fat deposition and proinflammatory responses compared with hepatocytes co-cultured with WT macrophages. CONCLUSIONS Pfkfb3 disruption only in hematopoietic cells exacerbates HFD-induced hepatic steatosis and inflammation whereas the Pfkfb3/iPfk2 in nonhematopoietic cells appeared to be needed for HFD feeding to induce hepatic steatosis. As such, the Pfkfb3/iPfk2 plays a unique role in regulating NAFLD pathophysiology.
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Affiliation(s)
- Xin Guo
- Department of Nutrition, Texas A&M University, College Station, TX, USA
- Department of Nutrition and Food Hygiene, School of Public Health, Cheeloo College of Medicine, Shandong University, Jinan, China
| | - Bilian Zhu
- Department of Nutrition, Texas A&M University, College Station, TX, USA
- Department of VIP Medical Service Center, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
| | - Hang Xu
- Department of Nutrition, Texas A&M University, College Station, TX, USA
| | - Honggui Li
- Department of Nutrition, Texas A&M University, College Station, TX, USA
| | - Boxiong Jiang
- Department of VIP Medical Service Center, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
| | - Yina Wang
- Department of VIP Medical Service Center, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
| | - Benrong Zheng
- Department of VIP Medical Service Center, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
| | - Shannon Glaser
- Medical Physiology, Texas A&M University College of Medicine, Bryan, TX, USA
| | - Gianfranco Alpini
- Hepatology and Gastroenterology, Medicine, Indiana University, Indianapolis, IN, USA
- Richard L. Roudebush VA Medical Center, Indianapolis, IN, USA
| | - Chaodong Wu
- Department of Nutrition, Texas A&M University, College Station, TX, USA
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Kunst RF, Niemeijer M, van der Laan LJW, Spee B, van de Graaf SFJ. From fatty hepatocytes to impaired bile flow: Matching model systems for liver biology and disease. Biochem Pharmacol 2020; 180:114173. [PMID: 32717228 DOI: 10.1016/j.bcp.2020.114173] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2020] [Revised: 07/21/2020] [Accepted: 07/22/2020] [Indexed: 02/08/2023]
Abstract
A large variety of model systems are used in hepatobiliary research. In this review, we aim to provide an overview of established and emerging models for specific research questions. We specifically discuss the value and limitations of these models for research on metabolic associated fatty liver disease (MAFLD), (previously named non-alcoholic fatty liver diseases/non-alcoholic steatohepatitis (NAFLD/NASH)) and cholestasis-related diseases such as primary biliary cholangitis (PBC) and primary sclerosing cholangitis (PSC). The entire range of models is discussed varying from immortalized cell lines, mature or pluripotent stem cell-based models including organoids/spheroids, to animal models and human ex vivo models such as normothermic machine perfusion of livers and living liver slices. Finally, the pros and cons of each model are discussed as well as the need in the scientific community for continuous innovation in model development to better mimic the human (patho)physiology.
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Affiliation(s)
- Roni F Kunst
- Tytgat Institute for Liver and Intestinal Research, Amsterdam Gastroenterology Endocrinology Metabolism, Amsterdam University Medical Centers, University of Amsterdam, Amsterdam, the Netherlands
| | - Marije Niemeijer
- Department of Surgery, Erasmus MC-University Medical Center, Rotterdam, the Netherlands; Division of Drug Discovery and Safety, Leiden Academic Centre for Drug Research, Leiden University, Leiden, the Netherlands
| | - Luc J W van der Laan
- Department of Surgery, Erasmus MC-University Medical Center, Rotterdam, the Netherlands
| | - Bart Spee
- Department of Clinical Sciences, Faculty of Veterinary Medicine, Utrecht University, Utrecht, the Netherlands
| | - Stan F J van de Graaf
- Tytgat Institute for Liver and Intestinal Research, Amsterdam Gastroenterology Endocrinology Metabolism, Amsterdam University Medical Centers, University of Amsterdam, Amsterdam, the Netherlands; Department of Gastroenterology and Hepatology, Amsterdam Gastroenterology Endocrinology Metabolism, Amsterdam University Medical Centers, University of Amsterdam, Amsterdam, the Netherlands.
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Ipsen DH, Lykkesfeldt J, Tveden-Nyborg P. Animal Models of Fibrosis in Nonalcoholic Steatohepatitis: Do They Reflect Human Disease? Adv Nutr 2020; 11:1696-1711. [PMID: 33191435 PMCID: PMC7666900 DOI: 10.1093/advances/nmaa081] [Citation(s) in RCA: 40] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/02/2020] [Revised: 05/06/2020] [Accepted: 06/11/2020] [Indexed: 12/12/2022] Open
Abstract
Nonalcoholic steatohepatitis (NASH) is one of the most common chronic liver diseases in the world, yet no pharmacotherapies are available. The lack of translational animal models is a major barrier impeding elucidation of disease mechanisms and drug development. Multiple preclinical models of NASH have been proposed and can broadly be characterized as diet-induced, deficiency-induced, toxin-induced, genetically induced, or a combination of these. However, very few models develop advanced fibrosis while still reflecting human disease etiology or pathology, which is problematic since fibrosis stage is considered the best prognostic marker in patients and an important endpoint in clinical trials of NASH. While mice and rats predominate the NASH research, several other species have emerged as promising models. This review critically evaluates animal models of NASH, focusing on their ability to develop advanced fibrosis while maintaining their relevance to the human condition.
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Affiliation(s)
- David H Ipsen
- Department of Veterinary and Animal Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Frederiksberg C, Denmark
| | - Jens Lykkesfeldt
- Department of Veterinary and Animal Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Frederiksberg C, Denmark
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Zhang L, Bansal MB. Role of Kupffer Cells in Driving Hepatic Inflammation and Fibrosis in HIV Infection. Front Immunol 2020; 11:1086. [PMID: 32612603 PMCID: PMC7308419 DOI: 10.3389/fimmu.2020.01086] [Citation(s) in RCA: 37] [Impact Index Per Article: 7.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/10/2020] [Accepted: 05/05/2020] [Indexed: 12/12/2022] Open
Abstract
While the interactions between HIV and various liver cell populations have been explored, the relevance of these interactions when patients are well-controlled on ART is less clear. Therefore, we focus this perspective on HIV-related alterations that may drive hepatic inflammation and fibrosis in aviremic patients, with a focus on Kupffer cells and Hepatic Stellate Cells. Persistent CD4+ T cell depletion in the gut resulting in increased gut permeability has been postulated to play a role in systemic immune activation in HIV patients. The liver, with its unique location, remains the gatekeeper between the gut and the systemic circulation. The resident liver macrophage, Kupffer cell, is responsible for clearing and responding to these products. We propose that changes in Kupffer cell biology, in the context of HIV infection, creates a mileu that drives hepatic inflammation and fibrosis in response to microbial translocation. Targeting these pathways may be helpful in improving liver-related outcomes in HIV patients.
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Affiliation(s)
- Lumin Zhang
- Divison of Liver Diseases, Icahn School of Medicine at Mount Sinai, New York, NY, United States
| | - Meena B Bansal
- Divison of Liver Diseases, Icahn School of Medicine at Mount Sinai, New York, NY, United States
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Li Y, Li N, Liu J, An X. Gr-1 highLy6G +Myeloid-derived suppressor cells and their role in a murine model of non-alcoholic steatohepatitis. Am J Transl Res 2020; 12:2827-2842. [PMID: 32655813 PMCID: PMC7344062] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/06/2019] [Accepted: 05/21/2020] [Indexed: 06/11/2023]
Abstract
BACKGROUND AND AIM Myeloid-derived suppressor cells are a heterogeneous cell population that expand during several pathogenic conditions. However, their role in non-alcoholic steatohepatitis remains unclear. This study aimed to examine the systemic effects of myeloid-derived suppressor cells, to determine the role of Gr-1highLy6G+MDSCs and their correlation with the CXCL12/CXCR4 axis in non-alcoholic steatohepatitis. METHODS We established a non-alcoholic steatohepatitis model and detected inflammatory factors IL-6, PGE2, and INF-γ, using an enzyme-linked immunosorbent assay. Proportions of lymphocyte subsets in peripheral blood, CD11b+Gr-1+myeloid-derived suppressor cells and its subsets in the blood, spleen, liver, and bone marrow were identified using flow cytometry. Adoptive transfer and depletion experiments for MDSCs were performed. Immunohistochemistry, migration assays, and in vivo experiments were used to analyze the role of CXCL12/CXCR4 in non-alcoholic steatohepatitis. RESULTS The proportion of CD11b+Gr-1+MDSCs changed in the bone marrow, spleen, blood, and liver in the non-alcoholic steatohepatitis model. CD4+ and CD8+ T lymphocytes were significantly reduced in non-alcoholic steatohepatitis. Compared with control mice, a significant decrease in ALT and AST levels was observed in Gr-1highLy6G+MDSCs-treated model mice. The migration ability of AMD3100-treated MDSCs was significantly reduced, but was restored as CXCL12 levels increased. CXCL12 and CXCR4 protein levels increased significantly in the non-alcoholic steatohepatitis livers. CONCLUSIONS Exogenous Gr-1highLy6G+MDSCs improved liver function during non-alcoholic steatohepatitis. The CXCR4/CXCL12 axis could be the key pathway mediating the attraction of myeloid-derived suppressor cells into the non-alcoholic steatohepatitis environment in mice.
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Affiliation(s)
- Yue Li
- Department of Gastroenterology, First Hospital of Shanxi Medical UniversityTaiyuan, Shanxi, P. R. China
- Shanxi Medical UniversityTaiyuan, Shanxi, P. R. China
| | - Ning Li
- Department of Pathology, First Hospital of Shanxi Medical UniversityTaiyuan, Shanxi, P. R. China
| | - Jinchun Liu
- Department of Gastroenterology, First Hospital of Shanxi Medical UniversityTaiyuan, Shanxi, P. R. China
| | - Xiuqin An
- Shanxi Medical UniversityTaiyuan, Shanxi, P. R. China
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Novo E, Bocca C, Foglia B, Protopapa F, Maggiora M, Parola M, Cannito S. Liver fibrogenesis: un update on established and emerging basic concepts. Arch Biochem Biophys 2020; 689:108445. [PMID: 32524998 DOI: 10.1016/j.abb.2020.108445] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/27/2020] [Revised: 05/20/2020] [Accepted: 05/28/2020] [Indexed: 02/06/2023]
Abstract
Liver fibrogenesis is defined as a dynamic and highly integrated process occurring during chronic injury to liver parenchyma that can result in excess deposition of extracellular matrix (ECM) components (i.e., liver fibrosis). Liver fibrogenesis, together with chronic inflammatory response, is then primarily involved in the progression of chronic liver diseases (CLD) irrespective of the specific etiology. In the present review we will first offer a synthetic and updated overview of major basic concepts in relation to the role of myofibroblasts (MFs), macrophages and other hepatic cell populations involved in CLD to then offer an overview of established and emerging issues and mechanisms that have been proposed to favor and/or promote CLD progression. A special focus will be dedicated to selected issues that include emerging features in the field of cholangiopathies, the emerging role of genetic and epigenetic factors as well as of hypoxia, hypoxia-inducible factors (HIFs) and related mediators.
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Affiliation(s)
- Erica Novo
- University of Torino, Dept. Clinical and Biological Sciences, Unit of Experimental Medicine and Clinical Pathology, Corso Raffaello 30, 10125, Torino, Italy
| | - Claudia Bocca
- University of Torino, Dept. Clinical and Biological Sciences, Unit of Experimental Medicine and Clinical Pathology, Corso Raffaello 30, 10125, Torino, Italy
| | - Beatrice Foglia
- University of Torino, Dept. Clinical and Biological Sciences, Unit of Experimental Medicine and Clinical Pathology, Corso Raffaello 30, 10125, Torino, Italy
| | - Francesca Protopapa
- University of Torino, Dept. Clinical and Biological Sciences, Unit of Experimental Medicine and Clinical Pathology, Corso Raffaello 30, 10125, Torino, Italy
| | - Marina Maggiora
- University of Torino, Dept. Clinical and Biological Sciences, Unit of Experimental Medicine and Clinical Pathology, Corso Raffaello 30, 10125, Torino, Italy
| | - Maurizio Parola
- University of Torino, Dept. Clinical and Biological Sciences, Unit of Experimental Medicine and Clinical Pathology, Corso Raffaello 30, 10125, Torino, Italy.
| | - Stefania Cannito
- University of Torino, Dept. Clinical and Biological Sciences, Unit of Experimental Medicine and Clinical Pathology, Corso Raffaello 30, 10125, Torino, Italy
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Bruschi FV, Tardelli M, Herac M, Claudel T, Trauner M. Metabolic regulation of hepatic PNPLA3 expression and severity of liver fibrosis in patients with NASH. Liver Int 2020; 40:1098-1110. [PMID: 32043752 PMCID: PMC7318357 DOI: 10.1111/liv.14402] [Citation(s) in RCA: 23] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/23/2019] [Revised: 01/31/2020] [Accepted: 02/03/2020] [Indexed: 02/06/2023]
Abstract
BACKGROUND AND AIMS The genetic PNPLA3 polymorphism I148M has been extensively associated with higher risk for development and progression of NAFLD towards NASH. METHODS PNPLA3 and α-SMA expression were quantified in liver biopsies collected from NASH patients (n = 26) with different fibrosis stages and PNPLA3 genotypes. To study the potential mechanisms driving PNPLA3 expression during NASH progression towards fibrosis, hepatocytes and hepatic stellate cells (HSCs) were cultivated in low and high glucose medium. Moreover, hepatocytes were treated with increasing concentrations of palmitic acid alone or in combination with glucose. Conditioned media were collected from challenged hepatocytes to stimulate HSCs. RESULTS Tissue expression of PNPLA3 was significantly enhanced in biopsies of patients carrying the I148M polymorphism compared to wild type (WT). In NASH biopsies, PNPLA3 significantly correlated with fibrosis stage and α-SMA levels independently of PNPLA3 genotype. In line, PNPLA3 expression was higher in α-SMA positive cells. Low glucose increased PNPLA3 in HSCs, whereas high glucose induced PNPLA3 and de-novo lipogenesis-related genes expression in hepatocytes. Palmitic acid induced fat accumulation and cell stress markers in hepatocytes, which could be counteracted by oleic acid. Conditioned media collected from lipotoxic challenged hepatocytes markedly induced PNPLA3 mRNA and protein levels, fibrogenic and autophagic markers and promoted migration in HSCs. Notably, conditioned media collected from hepatocytes cultivated with both glucose and palmitic acid exacerbated HSCs migration, PNPLA3 and fibrogenic gene expression, promoting release of cytokines from HSCs. CONCLUSIONS Collectively, our observations uncover the diverse metabolic regulation of PNPLA3 among different hepatic cell populations and support its relation to fibrosis progression.
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Affiliation(s)
- Francesca V. Bruschi
- Hans Popper Laboratory of Molecular HepatologyDivision of Gastroenterology and HepatologyInternal Medicine IIIMedical University of ViennaViennaAustria
| | - Matteo Tardelli
- Hans Popper Laboratory of Molecular HepatologyDivision of Gastroenterology and HepatologyInternal Medicine IIIMedical University of ViennaViennaAustria,Division of Gastroenterology and HepatologyJoan and Sanford I. Weill Cornell Department of MedicineWeill Cornell Medical CollegeNew YorkNYUSA
| | - Merima Herac
- Clinical Institute of PathologyMedical University of ViennaViennaAustria
| | - Thierry Claudel
- Hans Popper Laboratory of Molecular HepatologyDivision of Gastroenterology and HepatologyInternal Medicine IIIMedical University of ViennaViennaAustria
| | - Michael Trauner
- Hans Popper Laboratory of Molecular HepatologyDivision of Gastroenterology and HepatologyInternal Medicine IIIMedical University of ViennaViennaAustria
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50
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Wu L, Sun J, Liu L, Du X, Liu Y, Yan X, Kombo Osoro E, Zhang F, Feng L, Liang D, Li Y, Chen Q, Sun S, Zhang L, Lan X, Li D, Lu S. Anti-toll-like receptor 2 antibody ameliorates hepatic injury, inflammation, fibrosis and steatosis in obesity-related metabolic disorder rats via regulating MAPK and NF-κB pathways. Int Immunopharmacol 2020; 82:106368. [PMID: 32151955 DOI: 10.1016/j.intimp.2020.106368] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/02/2020] [Revised: 02/28/2020] [Accepted: 02/29/2020] [Indexed: 02/06/2023]
Abstract
Nonalcoholic fatty liver disease (NAFLD) is one of the most common liver diseases worldwide, which includes a spectrum of histological liver changes. Non-alcoholic steatohepatitis (NASH) is considered to be the progressive subtype of NAFLD, which is characterized by lobular inflammation and cellular ballooning on the basis of steatosis. There is a critical need to develop novel and effective therapeutic approaches for NAFLD/NASH. The activation of toll-like receptor 2 (TLR2) signaling pathway plays a key role in high-fat-related inflammation, triggering the occurrence and development of NASH. Herein, the anti-TLR2 monoclonal antibody (TLR2 mAb) was prepared and investigated for its ability to ameliorate the inflammatory response in vivo and in vitro. The anti-inflammatory role of TLR2 mAb in vitro was examined in NR8383 macrophage cells and THP-1 derived macrophage cells. For confirmation in vivo, three groups of SD rats were treated for 20 weeks: rats in the control were fed with a standard diet; rates in the IgG and TLR2 mAb groups were fed with a high-fat diet and with IgG or TLR2 mAb, respectively. Liver tissue and serum were collected for further analysis. Results showed that after 4-week treatment with TLR2 mAb, metabolic parameters in rats were improved markedly (body weight, fasting blood glucose level, liver steatosis, inflammatory response and fibrosis). Moreover, western blotting demonstrated that the TLR2 mAb blocked MAPKs and NF-κB activation, and inhibited the expression of inflammatory factors in rat liver tissue. These effects suggested that TLR2 mAb could improve HFD-induced hepatic injury, inflammation, fibrosis and steatosis by suppressing inflammatory response and regulating the hepatic MAPKs and NF-κB signaling pathways. This suggests that TLR2 may be a novel therapeutic target for metabolic diseases especially NASH.
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Affiliation(s)
- Litao Wu
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Xi'an Jiaotong University Health Science Center, Xi'an, Shaanxi 710061, PR China; Key Laboratory of Environment and Genes Related to Diseases (Xi'an Jiaotong University), Ministry of Education of China, Xi'an, Shaanxi 710061, PR China
| | - Juan Sun
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Xi'an Jiaotong University Health Science Center, Xi'an, Shaanxi 710061, PR China; Key Laboratory of Environment and Genes Related to Diseases (Xi'an Jiaotong University), Ministry of Education of China, Xi'an, Shaanxi 710061, PR China
| | - Li Liu
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Xi'an Jiaotong University Health Science Center, Xi'an, Shaanxi 710061, PR China; Key Laboratory of Environment and Genes Related to Diseases (Xi'an Jiaotong University), Ministry of Education of China, Xi'an, Shaanxi 710061, PR China; Department of Pathology, Sunshine Union Hospital, Weifang, Shandong Province 261061, PR China
| | - Xiaojuan Du
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Xi'an Jiaotong University Health Science Center, Xi'an, Shaanxi 710061, PR China; Key Laboratory of Environment and Genes Related to Diseases (Xi'an Jiaotong University), Ministry of Education of China, Xi'an, Shaanxi 710061, PR China
| | - Yan Liu
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Xi'an Jiaotong University Health Science Center, Xi'an, Shaanxi 710061, PR China; Key Laboratory of Environment and Genes Related to Diseases (Xi'an Jiaotong University), Ministry of Education of China, Xi'an, Shaanxi 710061, PR China
| | - Xiaofei Yan
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Xi'an Jiaotong University Health Science Center, Xi'an, Shaanxi 710061, PR China; Key Laboratory of Environment and Genes Related to Diseases (Xi'an Jiaotong University), Ministry of Education of China, Xi'an, Shaanxi 710061, PR China
| | - Ezra Kombo Osoro
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Xi'an Jiaotong University Health Science Center, Xi'an, Shaanxi 710061, PR China; Key Laboratory of Environment and Genes Related to Diseases (Xi'an Jiaotong University), Ministry of Education of China, Xi'an, Shaanxi 710061, PR China
| | - Fujun Zhang
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Xi'an Jiaotong University Health Science Center, Xi'an, Shaanxi 710061, PR China; Key Laboratory of Environment and Genes Related to Diseases (Xi'an Jiaotong University), Ministry of Education of China, Xi'an, Shaanxi 710061, PR China
| | - Lina Feng
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Xi'an Jiaotong University Health Science Center, Xi'an, Shaanxi 710061, PR China; Key Laboratory of Environment and Genes Related to Diseases (Xi'an Jiaotong University), Ministry of Education of China, Xi'an, Shaanxi 710061, PR China
| | - Dong Liang
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Xi'an Jiaotong University Health Science Center, Xi'an, Shaanxi 710061, PR China; Key Laboratory of Environment and Genes Related to Diseases (Xi'an Jiaotong University), Ministry of Education of China, Xi'an, Shaanxi 710061, PR China
| | - Yazhao Li
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Xi'an Jiaotong University Health Science Center, Xi'an, Shaanxi 710061, PR China; Key Laboratory of Environment and Genes Related to Diseases (Xi'an Jiaotong University), Ministry of Education of China, Xi'an, Shaanxi 710061, PR China
| | - Qian Chen
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Xi'an Jiaotong University Health Science Center, Xi'an, Shaanxi 710061, PR China; Key Laboratory of Environment and Genes Related to Diseases (Xi'an Jiaotong University), Ministry of Education of China, Xi'an, Shaanxi 710061, PR China
| | - Sha Sun
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Xi'an Jiaotong University Health Science Center, Xi'an, Shaanxi 710061, PR China; Key Laboratory of Environment and Genes Related to Diseases (Xi'an Jiaotong University), Ministry of Education of China, Xi'an, Shaanxi 710061, PR China
| | - Lei Zhang
- MOE Key Laboratory for Nonequilibrium Synthesis and Modulation of Condensed Matter, School of Science, Xi'an Jiaotong University, Xi'an, Shaanxi 710049, PR China
| | - Xi Lan
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Xi'an Jiaotong University Health Science Center, Xi'an, Shaanxi 710061, PR China; Key Laboratory of Environment and Genes Related to Diseases (Xi'an Jiaotong University), Ministry of Education of China, Xi'an, Shaanxi 710061, PR China.
| | - Dongmin Li
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Xi'an Jiaotong University Health Science Center, Xi'an, Shaanxi 710061, PR China; Key Laboratory of Environment and Genes Related to Diseases (Xi'an Jiaotong University), Ministry of Education of China, Xi'an, Shaanxi 710061, PR China.
| | - Shemin Lu
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Xi'an Jiaotong University Health Science Center, Xi'an, Shaanxi 710061, PR China; Key Laboratory of Environment and Genes Related to Diseases (Xi'an Jiaotong University), Ministry of Education of China, Xi'an, Shaanxi 710061, PR China
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