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Chen C, Wang L. Aging and metabolic dysfunction-associated steatotic liver disease: a bidirectional relationship. Front Med 2025:10.1007/s11684-025-1133-7. [PMID: 40316793 DOI: 10.1007/s11684-025-1133-7] [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: 10/28/2024] [Accepted: 01/09/2025] [Indexed: 05/04/2025]
Abstract
In recent years, aging and cellular senescence have triggered an increased interest in corresponding research fields. Evidence shows that the complex aging process is involved in the development of many chronic liver diseases, such as metabolic dysfunction-associated steatotic liver disease (MASLD) and metabolic dysfunction-associated steatohepatitis (MASH). In fact, aging has a tremendous effect on the liver, leading to a gradual decline in the metabolism, detoxification and immune functions of the liver, which in turn increases the risk of liver disease. These changes can be based on the aging of liver cells (hepatocytes, liver sinusoidal endothelial cells, hepatic stellate cells, and Kupffer cells). Similarly, patients with liver diseases exhibit increases in the aging phenotype and aging cells, often manifesting as faster physical functional decline, which is closely related to the promoting effect of liver disease on aging. This review summarizes the interplay between MASLD/MASH development and aging, aiming to reveal the complex relationships that exacerbate one another. Moreover, the corresponding schemes for delaying aging or treating diseases are discussed to provide a basis for the development of effective prevention and treatment strategies in the future.
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Affiliation(s)
- Chen Chen
- Department of Hepatobiliary Surgery, Xi-Jing Hospital, Fourth Military Medical University, Xi'an, 710032, China
| | - Lin Wang
- Department of Hepatobiliary Surgery, Xi-Jing Hospital, Fourth Military Medical University, Xi'an, 710032, China.
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Zhang X, Lau HCH, Ha S, Liu C, Liang C, Lee HW, Ng QWY, Zhao Y, Ji F, Zhou Y, Pan Y, Song Y, Zhang Y, Lo JCY, Cheung AHK, Wu J, Li X, Xu H, Wong CC, Wong VWS, Yu J. Intestinal TM6SF2 protects against metabolic dysfunction-associated steatohepatitis through the gut-liver axis. Nat Metab 2025; 7:102-119. [PMID: 39779889 PMCID: PMC11774752 DOI: 10.1038/s42255-024-01177-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/18/2023] [Accepted: 11/14/2024] [Indexed: 01/11/2025]
Abstract
Transmembrane-6 superfamily member 2 (TM6SF2) regulates hepatic fat metabolism and is associated with metabolic dysfunction-associated steatohepatitis (MASH). TM6SF2 genetic variants are associated with steatotic liver disease. The pathogenesis of MASH involves genetic factors and gut microbiota alteration, yet the role of host-microbe interactions in MASH development remains unclear. Here, we discover that mice with intestinal epithelial cell-specific knockout of Tm6sf2 (Tm6sf2ΔIEC) develop MASH, accompanied by impaired intestinal barrier and microbial dysbiosis. Transplanting stools from Tm6sf2ΔIEC mice induces steatohepatitis in germ-free recipient mice, whereas MASH is alleviated in Tm6sf2ΔIEC mice co-housed with wild-type mice. Mechanistically, Tm6sf2-deficient intestinal cells secrete more free fatty acids by interacting with fatty acid-binding protein 5 to induce intestinal barrier dysfunction, enrichment of pathobionts, and elevation of lysophosphatidic acid (LPA) levels. LPA is translocated from the gut to the liver, contributing to lipid accumulation and inflammation. Pharmacological inhibition of the LPA receptor suppresses MASH in both Tm6sf2ΔIEC and wild-type mice. Hence, modulating microbiota or blocking the LPA receptor is a potential therapeutic strategy in TM6SF2 deficiency-induced MASH.
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Affiliation(s)
- Xiang Zhang
- Department of Medicine and Therapeutics, Institute of Digestive Disease, State Key Laboratory of Digestive Disease, Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Hong Kong SAR, China
| | - Harry Cheuk-Hay Lau
- Department of Medicine and Therapeutics, Institute of Digestive Disease, State Key Laboratory of Digestive Disease, Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Hong Kong SAR, China
| | - Suki Ha
- Department of Medicine and Therapeutics, Institute of Digestive Disease, State Key Laboratory of Digestive Disease, Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Hong Kong SAR, China
| | - Chuanfa Liu
- Department of Medicine and Therapeutics, Institute of Digestive Disease, State Key Laboratory of Digestive Disease, Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Hong Kong SAR, China
| | - Cong Liang
- Institute of Precision Medicine, First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | - Hye Won Lee
- Department of Internal Medicine, Institute of Gastroenterology, Yonsei University College of Medicine, Seoul, South Korea
| | - Queena Wing-Yin Ng
- Department of Medicine and Therapeutics, Institute of Digestive Disease, State Key Laboratory of Digestive Disease, Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Hong Kong SAR, China
| | - Yi Zhao
- Department of Medicine and Therapeutics, Institute of Digestive Disease, State Key Laboratory of Digestive Disease, Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Hong Kong SAR, China
- Institute of Precision Medicine, First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | - Fenfen Ji
- Department of Medicine and Therapeutics, Institute of Digestive Disease, State Key Laboratory of Digestive Disease, Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Hong Kong SAR, China
| | - Yunfei Zhou
- Department of Medicine and Therapeutics, Institute of Digestive Disease, State Key Laboratory of Digestive Disease, Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Hong Kong SAR, China
| | - Yasi Pan
- Department of Medicine and Therapeutics, Institute of Digestive Disease, State Key Laboratory of Digestive Disease, Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Hong Kong SAR, China
| | - Yang Song
- Department of Medicine and Therapeutics, Institute of Digestive Disease, State Key Laboratory of Digestive Disease, Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Hong Kong SAR, China
- Department of Gastroenterology, Zhongshan Hospital, Xiamen University, Xiamen, China
| | - Yating Zhang
- Department of Medicine and Therapeutics, Institute of Digestive Disease, State Key Laboratory of Digestive Disease, Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Hong Kong SAR, China
| | - Jennie Ching Yin Lo
- Department of Medicine and Therapeutics, Institute of Digestive Disease, State Key Laboratory of Digestive Disease, Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Hong Kong SAR, China
| | - Alvin Ho Kwan Cheung
- Department of Anatomical and Cellular Pathology, The Chinese University of Hong Kong, Hong Kong SAR, China
| | - Jianfeng Wu
- State Key Laboratory of Cellular Stress Biology, School of Medicine, Xiamen University, Xiamen, China
| | - Xiaoxing Li
- Institute of Precision Medicine, First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | - Hongzhi Xu
- Department of Gastroenterology, Zhongshan Hospital, Xiamen University, Xiamen, China
| | - Chi Chun Wong
- Department of Medicine and Therapeutics, Institute of Digestive Disease, State Key Laboratory of Digestive Disease, Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Hong Kong SAR, China
| | - Vincent Wai-Sun Wong
- Department of Medicine and Therapeutics, Institute of Digestive Disease, State Key Laboratory of Digestive Disease, Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Hong Kong SAR, China.
| | - Jun Yu
- Department of Medicine and Therapeutics, Institute of Digestive Disease, State Key Laboratory of Digestive Disease, Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Hong Kong SAR, China.
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Zhu Y, Shang L, Tang Y, Li Q, Ding L, Wang Y, Zhang T, Xie B, Ma J, Li X, Chen S, Yi X, Peng J, Liang Y, He A, Yan H, Zhu H, Zhang B, Zhu Y. Genome-Wide Profiling of H3K27ac Identifies TDO2 as a Pivotal Therapeutic Target in Metabolic Associated Steatohepatitis Liver Disease. ADVANCED SCIENCE (WEINHEIM, BADEN-WURTTEMBERG, GERMANY) 2024; 11:e2404224. [PMID: 39364706 PMCID: PMC11615751 DOI: 10.1002/advs.202404224] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/21/2024] [Revised: 09/13/2024] [Indexed: 10/05/2024]
Abstract
H3K27ac has been widely recognized as a representative epigenetic marker of active enhancer, while its regulatory mechanisms in pathogenesis of metabolic dysfunction-associated steatotic liver disease (MASLD) remain elusive. Here, a genome-wide comparative study on H3K27ac activities and transcriptome profiling in high fat diet (HFD)-induced MASLD model is performed. A significantly enhanced H3K27ac density with abundant alterations of regulatory transcriptome is observed in MASLD rats. Based on integrative analysis of ChIP-Seq and RNA-Seq, TDO2 is identified as a critical contributor for abnormal lipid accumulation, transcriptionally activated by YY1-promoted H3K27ac. Furthermore, TDO2 depletion effectively protects against hepatic steatosis. In terms of mechanisms, TDO2 activates NF-κB pathway to promote macrophages M1 polarization, representing a crucial event in MASLD progression. A bovine serum albumin nanoparticle is fabricated to provide sustained release of Allopurinol (NPs-Allo) for TDO2 inhibition, possessing excellent biocompatibility and desired targeting capacity. Venous injection of NPs-Allo robustly alleviates HFD-induced metabolic disorders. This study reveals the pivotal role of TDO2 and its underlying mechanisms in pathogenesis of MASLD epigenetically and genetically. Targeting H3K27ac-TDO2-NF-κB axis may provide new insights into the pathogenesis of abnormal lipid accumulation and pave the way for developing novel strategies for MASLD prevention and treatment.
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Affiliation(s)
- Yaling Zhu
- Department of PathophysiologySchool of Basic Medical SciencesAnhui Medical UniversityHefeiAnhui230032China
| | - Limeng Shang
- Department of PathophysiologySchool of Basic Medical SciencesAnhui Medical UniversityHefeiAnhui230032China
| | - Yunshu Tang
- Laboratory Animal Research CenterSchool of Basic Medical SciencesAnhui Medical UniversityHefeiAnhui230032China
| | - Qiushuang Li
- Department of PathophysiologySchool of Basic Medical SciencesAnhui Medical UniversityHefeiAnhui230032China
| | - Lin Ding
- Department of PathophysiologySchool of Basic Medical SciencesAnhui Medical UniversityHefeiAnhui230032China
| | - Yi Wang
- Department of PathophysiologySchool of Basic Medical SciencesAnhui Medical UniversityHefeiAnhui230032China
| | - Tiantian Zhang
- Department of PathophysiologySchool of Basic Medical SciencesAnhui Medical UniversityHefeiAnhui230032China
| | - Bin Xie
- Department of PathophysiologySchool of Basic Medical SciencesAnhui Medical UniversityHefeiAnhui230032China
| | - Jinhu Ma
- Department of PathophysiologySchool of Basic Medical SciencesAnhui Medical UniversityHefeiAnhui230032China
| | - Xinyu Li
- Department of PathophysiologySchool of Basic Medical SciencesAnhui Medical UniversityHefeiAnhui230032China
| | - Shuwen Chen
- Department of PathophysiologySchool of Basic Medical SciencesAnhui Medical UniversityHefeiAnhui230032China
| | - Xinrui Yi
- Department of PathophysiologySchool of Basic Medical SciencesAnhui Medical UniversityHefeiAnhui230032China
| | - Jin Peng
- Department of PathophysiologySchool of Basic Medical SciencesAnhui Medical UniversityHefeiAnhui230032China
| | - Youfeng Liang
- Department of CardiologyThe First Affiliated Hospital of Anhui Medical UniversityHefeiAnhui230001China
| | - Anyuan He
- School of Life SciencesAnhui Medical UniversityHefeiAnhui230032China
| | - Hong Yan
- Department of PathologyThe First Affiliated Hospital of USTCDivision of Life Sciences and MedicineUniversity of Science and Technology of ChinaHefeiAnhui230001China
- Department of PathologySchool of Basic Medical SciencesSouthern Medical UniversityGuangzhouGuangdong510515China
| | - Huaqing Zhu
- Laboratory of Molecular Biology and Department of BiochemistryAnhui Medical UniversityHefeiAnhui230032China
| | - Buchun Zhang
- Department of CardiologyThe First Affiliated Hospital of USTCDivision of Life Sciences and MedicineUniversity of Science and Technology of ChinaHefeiAnhui230001China
| | - Yong Zhu
- Department of PathophysiologySchool of Basic Medical SciencesAnhui Medical UniversityHefeiAnhui230032China
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Drummer C, Saaoud F, Jhala NC, Cueto R, Sun Y, Xu K, Shao Y, Lu Y, Shen H, Yang L, Zhou Y, Yu J, Wu S, Snyder NW, Hu W, Zhuo J‘J, Zhong Y, Jiang X, Wang H, Yang X. Caspase-11 promotes high-fat diet-induced NAFLD by increasing glycolysis, OXPHOS, and pyroptosis in macrophages. Front Immunol 2023; 14:1113883. [PMID: 36776889 PMCID: PMC9909353 DOI: 10.3389/fimmu.2023.1113883] [Citation(s) in RCA: 41] [Impact Index Per Article: 20.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/01/2022] [Accepted: 01/06/2023] [Indexed: 01/27/2023] Open
Abstract
Introduction Non-alcoholic fatty liver disease (NAFLD) has a global prevalence of 25% of the population and is a leading cause of cirrhosis and hepatocellular carcinoma. NAFLD ranges from simple steatosis (non-alcoholic fatty liver) to non-alcoholic steatohepatitis (NASH). Hepatic macrophages, specifically Kupffer cells (KCs) and monocyte-derived macrophages, act as key players in the progression of NAFLD. Caspases are a family of endoproteases that provide critical connections to cell regulatory networks that sense disease risk factors, control inflammation, and mediate inflammatory cell death (pyroptosis). Caspase-11 can cleave gasdermin D (GSDMD) to induce pyroptosis and specifically defends against bacterial pathogens that invade the cytosol. However, it's still unknown whether high fat diet (HFD)-facilitated gut microbiota-generated cytoplasmic lipopolysaccharides (LPS) activate caspase-11 and promote NAFLD. Methods To examine this hypothesis, we performed liver pathological analysis, RNA-seq, FACS, Western blots, Seahorse mitochondrial stress analyses of macrophages and bone marrow transplantation on HFD-induced NAFLD in WT and Casp11-/- mice. Results and Discussion Our results showed that 1) HFD increases body wight, liver wight, plasma cholesterol levels, liver fat deposition, and NAFLD activity score (NAS score) in wild-type (WT) mice; 2) HFD increases the expression of caspase-11, GSDMD, interleukin-1β, and guanylate-binding proteins in WT mice; 3) Caspase-11 deficiency decreases fat liver deposition and NAS score; 4) Caspase-11 deficiency decreases bone marrow monocyte-derived macrophage (MDM) pyroptosis (inflammatory cell death) and inflammatory monocyte (IM) surface GSDMD expression; 5) Caspase-11 deficiency re-programs liver transcriptomes and reduces HFD-induced NAFLD; 6) Caspase-11 deficiency decreases extracellular acidification rates (glycolysis) and oxidative phosphorylation (OXPHOS) in inflammatory fatty acid palmitic acid-stimulated macrophages, indicating that caspase-11 significantly contributes to maintain dual fuel bioenergetics-glycolysis and OXPHOS for promoting pyroptosis in macrophages. These results provide novel insights on the roles of the caspase-11-GSDMD pathway in promoting hepatic macrophage inflammation and pyroptosis and novel targets for future therapeutic interventions involving the transition of NAFLD to NASH, hyperlipidemia, type II diabetes, metabolic syndrome, metabolically healthy obesity, atherosclerotic cardiovascular diseases, autoimmune diseases, liver transplantation, and hepatic cancers.
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Affiliation(s)
- Charles Drummer
- Centers of Cardiovascular Research, Temple University Lewis Katz School of Medicine, Philadelphia, PA, United States
| | - Fatma Saaoud
- Centers of Cardiovascular Research, Temple University Lewis Katz School of Medicine, Philadelphia, PA, United States
| | - Nirag C. Jhala
- Department of Pathology and Laboratory Medicine, Temple University Lewis Katz School of Medicine, Philadelphia, PA, United States
| | - Ramon Cueto
- Metabolic Disease Research and Thrombosis Research Center, Departments of Cardiovascular Sciences, Temple University Lewis Katz School of Medicine, Philadelphia, PA, United States
| | - Yu Sun
- Centers of Cardiovascular Research, Temple University Lewis Katz School of Medicine, Philadelphia, PA, United States
| | - Keman Xu
- Centers of Cardiovascular Research, Temple University Lewis Katz School of Medicine, Philadelphia, PA, United States
| | - Ying Shao
- Centers of Cardiovascular Research, Temple University Lewis Katz School of Medicine, Philadelphia, PA, United States
| | - Yifan Lu
- Centers of Cardiovascular Research, Temple University Lewis Katz School of Medicine, Philadelphia, PA, United States
| | - Huimin Shen
- Metabolic Disease Research and Thrombosis Research Center, Departments of Cardiovascular Sciences, Temple University Lewis Katz School of Medicine, Philadelphia, PA, United States
| | - Ling Yang
- Department of Medical Genetics and Molecular Biochemistry, Temple University Lewis Katz School of Medicine, Philadelphia, PA, United States
| | - Yan Zhou
- Biostatistics and Bioinformatics Facility, Fox Chase Cancer Center, Temple Health, Philadelphia, PA, United States
| | - Jun Yu
- Metabolic Disease Research and Thrombosis Research Center, Departments of Cardiovascular Sciences, Temple University Lewis Katz School of Medicine, Philadelphia, PA, United States
| | - Sheng Wu
- Metabolic Disease Research and Thrombosis Research Center, Departments of Cardiovascular Sciences, Temple University Lewis Katz School of Medicine, Philadelphia, PA, United States
| | - Nathaniel W. Snyder
- Metabolic Disease Research and Thrombosis Research Center, Departments of Cardiovascular Sciences, Temple University Lewis Katz School of Medicine, Philadelphia, PA, United States
| | - Wenhui Hu
- Metabolic Disease Research and Thrombosis Research Center, Departments of Cardiovascular Sciences, Temple University Lewis Katz School of Medicine, Philadelphia, PA, United States
| | - Jia ‘Joe’ Zhuo
- Tulane Hypertension & Renal Center of Excellence, Tulane University School of Medicine, New Orleans, LA, United States
| | - Yinghui Zhong
- School of Biomedical Engineering, Science and Health Systems, Drexel University, Philadelphia, PA, United States
| | - Xiaohua Jiang
- Metabolic Disease Research and Thrombosis Research Center, Departments of Cardiovascular Sciences, Temple University Lewis Katz School of Medicine, Philadelphia, PA, United States
| | - Hong Wang
- Metabolic Disease Research and Thrombosis Research Center, Departments of Cardiovascular Sciences, Temple University Lewis Katz School of Medicine, Philadelphia, PA, United States
| | - Xiaofeng Yang
- Centers of Cardiovascular Research, Temple University Lewis Katz School of Medicine, Philadelphia, PA, United States
- Metabolic Disease Research and Thrombosis Research Center, Departments of Cardiovascular Sciences, Temple University Lewis Katz School of Medicine, Philadelphia, PA, United States
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Yang B, Luo W, Wang M, Tang Y, Zhu W, Jin L, Wang M, Wang Y, Zhang Y, Zuo W, Huang LJ, Zhao Y, Liang G. Macrophage-specific MyD88 deletion and pharmacological inhibition prevents liver damage in non-alcoholic fatty liver disease via reducing inflammatory response. Biochim Biophys Acta Mol Basis Dis 2022; 1868:166480. [PMID: 35811033 DOI: 10.1016/j.bbadis.2022.166480] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/19/2022] [Revised: 06/14/2022] [Accepted: 06/28/2022] [Indexed: 02/06/2023]
Abstract
Activation of the innate immune system through toll-like receptors (TLRs) has been repeatedly demonstrated in non-alcoholic fatty liver disease (NAFLD) and several TLRs have been shown to contribute. Myeloid differentiation primary response 88 (MyD88) is as an adapter protein for the activation of TLRs and bridges TLRs to NF-κB-mediated inflammation in macrophages. However, whether myeloid cell MyD88 contributes to NAFLD are largely unknown. To test this approach, we generated macrophage-specific MyD88 knockout mice and show that these mice are protected against high-fat diet (HFD)-induced hepatic injury, lipid accumulation, and fibrosis. These protective effects were associated with reduced macrophage numbers in liver tissues and surpassed inflammatory responses. In cultured macrophages, saturated fatty acid palmitate utilizes MyD88 to activate NF-κB and induce inflammatory and fibrogenic factors. In hepatocytes, these factors may cause lipid accumulation and a further elaboration of inflammatory cytokines. In hepatic stellate cells, macrophage-derived factors, especially TGF-β, cause activation and hepatic fibrosis. We further show that pharmacological inhibition of MyD88 is also able to reduce NAFLD injury in HFD-fed mice. Therefore, our study has provided empirical evidence that macrophage MyD88 participates in HFD-induced NAFLD and could be targeted to prevent the development and progression of NAFLD/NASH.
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Affiliation(s)
- Bin Yang
- Chemical Biology Research Center, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang 325035, China
| | - Wu Luo
- Chemical Biology Research Center, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang 325035, China; Medical Research Center, the First Affiliated Hospital, Wenzhou Medical University, Wenzhou, Zhejiang 325035, China
| | - Minxiu Wang
- Chemical Biology Research Center, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang 325035, China
| | - Yelin Tang
- Chemical Biology Research Center, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang 325035, China
| | - Weiwei Zhu
- Chemical Biology Research Center, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang 325035, China
| | - Leiming Jin
- Chemical Biology Research Center, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang 325035, China
| | - Meihong Wang
- Chemical Biology Research Center, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang 325035, China
| | - Yi Wang
- Chemical Biology Research Center, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang 325035, China
| | - Yi Zhang
- School of Pharmaceutical Sciences, Hangzhou Medical College, Hangzhou, Zhejiang 311399, China
| | - Wei Zuo
- Affiliated Xiangshan Hospital of Wenzhou Medial University (Xiangshan First People's Hospital Medical and Health Group), Xiangshan, Zhejiang 315799, China
| | - Li-Jiang Huang
- Affiliated Xiangshan Hospital of Wenzhou Medial University (Xiangshan First People's Hospital Medical and Health Group), Xiangshan, Zhejiang 315799, China
| | - Yunjie Zhao
- Chemical Biology Research Center, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang 325035, China.
| | - Guang Liang
- Chemical Biology Research Center, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang 325035, China; School of Pharmaceutical Sciences, Hangzhou Medical College, Hangzhou, Zhejiang 311399, China.
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Geng A, Flint E, Bernsmeier C. Plasticity of monocytes and macrophages in cirrhosis of the liver. FRONTIERS IN NETWORK PHYSIOLOGY 2022; 2:937739. [PMID: 36926073 PMCID: PMC10013015 DOI: 10.3389/fnetp.2022.937739] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/06/2022] [Accepted: 06/27/2022] [Indexed: 06/06/2023]
Abstract
Cirrhosis of the liver is a systemic condition with raising prevalence worldwide. Patients with cirrhosis are highly susceptible to develop bacterial infections leading to acute decompensation and acute-on-chronic liver failure both associated with a high morbidity and mortality and sparse therapeutic options other than transplantation. Mononuclear phagocytes play a central role in innate immune responses and represent a first line of defence against pathogens. Their function includes phagocytosis, killing of bacteria, antigen presentation, cytokine production as well as recruitment and activation of immune effector cells. Liver injury and development of cirrhosis induces activation of liver resident Kupffer cells and recruitment of monocytes to the liver. Damage- and pathogen-associated molecular patterns promote systemic inflammation which involves multiple compartments besides the liver, such as the circulation, gut, peritoneal cavity and others. The function of circulating monocytes and tissue macrophages is severely impaired and worsens along with cirrhosis progression. The underlying mechanisms are complex and incompletely understood. Recent 'omics' technologies help to transform our understanding of cellular diversity and function in health and disease. In this review we point out the current state of knowledge on phenotypical and functional changes of monocytes and macrophages during cirrhosis evolution in different compartments and their role in disease progression. We also discuss the value of potential prognostic markers for cirrhosis-associated immuneparesis, and future immunotherapeutic strategies that may reduce the need for transplantation and death.
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Affiliation(s)
- Anne Geng
- Translational Hepatology, Department of Biomedicine, University of Basel, Basel, Switzerland
- Department of Biomedicine, University of Basel and University Centre for Gastrointestinal and Liver Diseases, Basel, Switzerland
| | - Emilio Flint
- Translational Hepatology, Department of Biomedicine, University of Basel, Basel, Switzerland
- Department of Biomedicine, University of Basel and University Centre for Gastrointestinal and Liver Diseases, Basel, Switzerland
| | - Christine Bernsmeier
- Translational Hepatology, Department of Biomedicine, University of Basel, Basel, Switzerland
- Department of Biomedicine, University of Basel and University Centre for Gastrointestinal and Liver Diseases, Basel, Switzerland
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Phillips BE, Lantier L, Engman C, Garciafigueroa Y, Singhi A, Trucco M, Mantzoros C, Wasserman D, Giannoukakis N. Improvement in insulin sensitivity and prevention of high fat diet-induced liver pathology using a CXCR2 antagonist. Cardiovasc Diabetol 2022; 21:130. [PMID: 35831885 PMCID: PMC9277870 DOI: 10.1186/s12933-022-01564-y] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/16/2022] [Accepted: 05/28/2022] [Indexed: 12/20/2022] Open
Abstract
BACKGROUND Liver pathology (LP) characteristic of non-alcoholic fatty acid disease (NAFLD)/non-alcoholic steatohepatitis (NASH) is a prevalent co-morbidity of type 2 diabetes (T2D). Accumulating evidence indicates that neutrophils driving insulin resistance (IR), including hepatic IR, precipitate T2D-associated NAFLD/NASH. We hypothesized that targeting neutrophil accumulation into insulin-sensitive tissues in mice using a CXCR2 antagonist under T2D-precipitating high fat diet (HFD) could improve insulin sensitivity and prevent the progression towards liver pathology reminiscent of NAFLD/NASH. METHODS Mice were age-matched and on standard rodent chow prior to 1:1 randomization into control and HFD formulated with the CXCR2 antagonist AZD5069 or with biologically inactive substitute. They were monitored for metabolic changes including insulin sensitivity using the hyperinsulinemic-euglycemic clamp and hepatic histopathologic evaluation in H&E-stained sections as well as via immunofluorescence microscopy of liver sections for leukocyte markers, collagen 1A1 formation, α-smooth muscle actin (SMA), and galectin-3 expression, for 16 weeks. Statistical tests used to determine significant differences among study groups and outcomes include Student's t-test, one-way ANOVA, repeated measures two-way ANOVA, and Fisher's exact test, depending on the analytical question. RESULTS Compared to mice on HFD, mice in the AZD5069-formulated HFD exhibited improved insulin sensitivity, a modest reduction in weight gain, and a significant improvement in LP and markers related to NAFLD/NASH. Mice in the AZD5069-formulated HFD also exhibited reduced neutrophil accumulation into the liver at the end of the 16 week study period. CONCLUSIONS These results show, for the first time, the effectiveness of a selective CXCR2 antagonist to improve insulin sensitivity, concomitantly preventing the progression towards LP characteristic of NAFLD/NASH. This represents a novel approach to target IR and developing LP under T2D-susceptible conditions using a single agent. Furthermore, our data extend the growing evidence in support of neutrophils as a leukocyte population that imprints and maintains a chronic inflammatory state in the progression of dysregulated metabolism in liver-specific co-morbid conditions.
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Affiliation(s)
- Brett E. Phillips
- Institute of Cellular Therapeutics, Allegheny Health Network, 11th Floor South Tower, 320 East North Avenue, Pittsburgh, PA S15212 USA
| | - Louise Lantier
- Department of Molecular Physiology and Biophysics, Vanderbilt University., Nashville, TN 37232 USA
| | - Carl Engman
- Institute of Cellular Therapeutics, Allegheny Health Network, 11th Floor South Tower, 320 East North Avenue, Pittsburgh, PA S15212 USA
| | - Yesica Garciafigueroa
- Institute of Cellular Therapeutics, Allegheny Health Network, 11th Floor South Tower, 320 East North Avenue, Pittsburgh, PA S15212 USA
| | - Aatur Singhi
- Department of Pathology, School of Medicine, Room A616.2, UPMC Presbyterian, University of Pittsburgh, 200 Lothrop Street, Pittsburgh, PA 15213 USA
| | - Massimo Trucco
- Institute of Cellular Therapeutics, Allegheny Health Network, 11th Floor South Tower, 320 East North Avenue, Pittsburgh, PA S15212 USA
| | - Christos Mantzoros
- Section of Endocrinology, VA Boston Healthcare System, Harvard Medical School, Boston, USA
- Department of Medicine Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA USA
| | - David Wasserman
- Department of Molecular Physiology and Biophysics, Vanderbilt University., Nashville, TN 37232 USA
| | - Nick Giannoukakis
- Institute of Cellular Therapeutics, Allegheny Health Network, 11th Floor South Tower, 320 East North Avenue, Pittsburgh, PA S15212 USA
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8
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Liu Z, Xiang H, Xiang D, Xiao S, Xiang H, Xiao J, Ren H, Hu P, Liu H, Peng M. Revealing potential anti-fibrotic mechanism of Ganxianfang formula based on RNA sequence. Chin Med 2022; 17:23. [PMID: 35180857 PMCID: PMC8855591 DOI: 10.1186/s13020-022-00579-7] [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: 10/27/2021] [Accepted: 02/01/2022] [Indexed: 11/18/2022] Open
Abstract
Background Ganxianfang (GXF) formula as a traditional Chinese medicine (TCM) is used for liver fibrosis in clinical practice while its mechanism is unclear. The aim of this study is to explore the molecular mechanism of GXF against CCl4-induced liver fibrosis rats. Methods Detected the main compounds of GXF by UPLC-MS/MS. Evaluated the efficacy of GXF (1.58, 3.15, 4.73 g/kg/day) and Fuzheng Huayu (FZHY, positive control, 0.47 g/kg/day) through serum alanine aminotransferase (ALT), aspartate aminotransferase (AST) levels and histopathological changes. Explored the underlying mechanisms by integrating our total liver RNA sequencing (RNA-seq) data with recent liver single-cell sequencing (scRNA-seq) studies. Verified potential pharmacodynamic substances of GXF by hepatic stellate cell (HSC)-T6 line. Results Main compounds were identified in GXF by UPLC-MS/MS, including baicalin, wogonoside and matrine etc. With GXF-high dose treatment, the elevation of ALT and AST induced by CCl4 were significantly reduced, and the protective effect of GXF-high dose treatment was better than FZHY. Liver histopathological changes were alleviated by GXF-high dose treatment, the ISHAK scoring showed the incidence of liver cirrhosis (F5/F6) decreased from 76.5 to 55.6%. The results of liver hydroxyproline content were consistent with the histopathological changes. RNA-seq analysis revealed the differential genes (DEGs) were mainly enriched in ECM-receptor interaction and chemokine signaling pathway. GXF effectively inhibited collagen deposition and significantly downregulated CCL2 to inhibit the recruitment of macrophages in liver tissue. Integrating scRNA-seq data revealed that GXF effectively inhibited the expansion of scar-associated Trem2+CD9+ macrophages subpopulation and PDGFRα+PDGFRβ+ scar-producing myofibroblasts in the damaged liver, and remodeled the fibrotic niche via regulation of ligand-receptor interactions including TGFβ/EGFR, PDGFB/PDGFRα, and TNFSF12/TNFRSF12a signaling. In vitro experiments demonstrated that baicalin, matrine and hesperidin in GXF inhibited the activation of hepatic stellate cells. Conclusions This study clarified the potential anti-fibrotic effects and molecular mechanism of GXF in CCl4-induced liver fibrosis rats, which deserves further promotion and application. Supplementary Information The online version contains supplementary material available at 10.1186/s13020-022-00579-7.
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Affiliation(s)
- Zongyi Liu
- Key Laboratory of Molecular Biology for Infectious Diseases (Ministry of Education), Institute for Viral Hepatitis, Department of Infectious Diseases, The Second Affiliated Hospital, Chongqing Medical University, Chongqing, 400010, China
| | - Huanyu Xiang
- Key Laboratory of Molecular Biology for Infectious Diseases (Ministry of Education), Institute for Viral Hepatitis, Department of Infectious Diseases, The Second Affiliated Hospital, Chongqing Medical University, Chongqing, 400010, China
| | - Dejuan Xiang
- Key Laboratory of Molecular Biology for Infectious Diseases (Ministry of Education), Institute for Viral Hepatitis, Department of Infectious Diseases, The Second Affiliated Hospital, Chongqing Medical University, Chongqing, 400010, China
| | - Shuang Xiao
- Key Laboratory of Molecular Biology for Infectious Diseases (Ministry of Education), Institute for Viral Hepatitis, Department of Infectious Diseases, The Second Affiliated Hospital, Chongqing Medical University, Chongqing, 400010, China
| | - Hongyan Xiang
- Key Laboratory of Molecular Biology for Infectious Diseases (Ministry of Education), Institute for Viral Hepatitis, Department of Infectious Diseases, The Second Affiliated Hospital, Chongqing Medical University, Chongqing, 400010, China
| | - Jing Xiao
- Key Laboratory of Molecular Biology for Infectious Diseases (Ministry of Education), Institute for Viral Hepatitis, Department of Infectious Diseases, The Second Affiliated Hospital, Chongqing Medical University, Chongqing, 400010, China
| | - Hong Ren
- Key Laboratory of Molecular Biology for Infectious Diseases (Ministry of Education), Institute for Viral Hepatitis, Department of Infectious Diseases, The Second Affiliated Hospital, Chongqing Medical University, Chongqing, 400010, China
| | - Peng Hu
- Key Laboratory of Molecular Biology for Infectious Diseases (Ministry of Education), Institute for Viral Hepatitis, Department of Infectious Diseases, The Second Affiliated Hospital, Chongqing Medical University, Chongqing, 400010, China
| | - Huabao Liu
- Department of Liver Diseases, Chongqing Traditional Chinese Medicine Hospital, Chongqing, 400021, China.
| | - Mingli Peng
- Key Laboratory of Molecular Biology for Infectious Diseases (Ministry of Education), Institute for Viral Hepatitis, Department of Infectious Diseases, The Second Affiliated Hospital, Chongqing Medical University, Chongqing, 400010, China.
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Understanding the Role of the Gut Microbiome and Microbial Metabolites in Non-Alcoholic Fatty Liver Disease: Current Evidence and Perspectives. Biomolecules 2021; 12:biom12010056. [PMID: 35053205 PMCID: PMC8774162 DOI: 10.3390/biom12010056] [Citation(s) in RCA: 159] [Impact Index Per Article: 39.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/14/2021] [Revised: 12/24/2021] [Accepted: 12/30/2021] [Indexed: 12/11/2022] Open
Abstract
Non-alcoholic fatty liver disease (NAFLD) is the most common chronic liver disease worldwide. NAFLD begins as a relatively benign hepatic steatosis which can evolve to non-alcoholic steatohepatitis (NASH); the risk of cirrhosis and hepatocellular carcinoma (HCC) increases when fibrosis is present. NAFLD represents a complex process implicating numerous factors—genetic, metabolic, and dietary—intertwined in a multi-hit etiopathogenetic model. Recent data have highlighted the role of gut dysbiosis, which may render the bowel more permeable, leading to increased free fatty acid absorption, bacterial migration, and a parallel release of toxic bacterial products, lipopolysaccharide (LPS), and proinflammatory cytokines that initiate and sustain inflammation. Although gut dysbiosis is present in each disease stage, there is currently no single microbial signature to distinguish or predict which patients will evolve from NAFLD to NASH and HCC. Using 16S rRNA sequencing, the majority of patients with NAFLD/NASH exhibit increased numbers of Bacteroidetes and differences in the presence of Firmicutes, resulting in a decreased F/B ratio in most studies. They also present an increased proportion of species belonging to Clostridium, Anaerobacter, Streptococcus, Escherichia, and Lactobacillus, whereas Oscillibacter, Flavonifaractor, Odoribacter, and Alistipes spp. are less prominent. In comparison to healthy controls, patients with NASH show a higher abundance of Proteobacteria, Enterobacteriaceae, and Escherichia spp., while Faecalibacterium prausnitzii and Akkermansia muciniphila are diminished. Children with NAFLD/NASH have a decreased proportion of Oscillospira spp. accompanied by an elevated proportion of Dorea, Blautia, Prevotella copri, and Ruminococcus spp. Gut microbiota composition may vary between population groups and different stages of NAFLD, making any conclusive or causative claims about gut microbiota profiles in NAFLD patients challenging. Moreover, various metabolites may be involved in the pathogenesis of NAFLD, such as short-chain fatty acids, lipopolysaccharide, bile acids, choline and trimethylamine-N-oxide, and ammonia. In this review, we summarize the role of the gut microbiome and metabolites in NAFLD pathogenesis, and we discuss potential preventive and therapeutic interventions related to the gut microbiome, such as the administration of probiotics, prebiotics, synbiotics, antibiotics, and bacteriophages, as well as the contribution of bariatric surgery and fecal microbiota transplantation in the therapeutic armamentarium against NAFLD. Larger and longer-term prospective studies, including well-defined cohorts as well as a multi-omics approach, are required to better identify the associations between the gut microbiome, microbial metabolites, and NAFLD occurrence and progression.
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Shi Y, Su W, Zhang L, Shi C, Zhou J, Wang P, Wang H, Shi X, Wei S, Wang Q, Auwerx J, Schoonjans K, Yu Y, Pan R, Zhou H, Lu L. TGR5 Regulates Macrophage Inflammation in Nonalcoholic Steatohepatitis by Modulating NLRP3 Inflammasome Activation. Front Immunol 2021; 11:609060. [PMID: 33692776 PMCID: PMC7937818 DOI: 10.3389/fimmu.2020.609060] [Citation(s) in RCA: 72] [Impact Index Per Article: 18.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/22/2020] [Accepted: 12/30/2020] [Indexed: 12/30/2022] Open
Abstract
Nonalcoholic steatohepatitis (NASH) is a chronic liver disease associated with dysregulation of liver metabolism and inflammation. G-protein coupled bile acid receptor 1 (TGR5) is a cell surface receptor that is involved in multiple metabolic pathways. However, the functions of TGR5 in regulating macrophage innate immune activation in NASH remain unclear. Here, we found that TGR5 expression was decreased in liver tissues from humans and mice with NASH. Compared to wild type (WT) mice, TGR5-knockout (TGR5-/-) mice exhibited exacerbated liver damage, increased levels of proinflammatory factors, and enhanced M1 macrophage polarization. Moreover, TGR5 deficiency facilitated M1 macrophage polarization by promoting NLRP3 inflammasome activation and caspase-1 cleavage. Taken together, our findings revealed that TGR5 signaling attenuated liver steatosis and inflammation and inhibited NLRP3-mediated M1 macrophage polarization in NASH.
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Affiliation(s)
- Yong Shi
- Jiangsu Key Laboratory of Molecular and Translational Cancer Research, The Affiliated Cancer Hospital (Jiangsu Cancer Hospital), Nanjing Medical University, Nanjing, China
- Hepatobiliary Center, The First Affiliated Hospital of Nanjing Medical University & Research Unit of Liver Transplantation and Transplant Immunology, Chinese Academy of Medical Sciences, Nanjing, China
- State Key Laboratory of Reproductive Medicine, Nanjing Medical University, Nanjing, China
- Jiangsu Collaborative Innovation Center of Biomedical Functional Materials, College of Chemistry and Materials Science, Nanjing Normal University, Nanjing, China
- Jiangsu Key Lab of Cancer Biomarkers, Prevention and Treatment, Collaborative Innovation Center for Personalized Cancer Medicine, Nanjing Medical University, Nanjing, China
| | - Wantong Su
- Jiangsu Key Laboratory of Molecular and Translational Cancer Research, The Affiliated Cancer Hospital (Jiangsu Cancer Hospital), Nanjing Medical University, Nanjing, China
- Hepatobiliary Center, The First Affiliated Hospital of Nanjing Medical University & Research Unit of Liver Transplantation and Transplant Immunology, Chinese Academy of Medical Sciences, Nanjing, China
- State Key Laboratory of Reproductive Medicine, Nanjing Medical University, Nanjing, China
- Jiangsu Collaborative Innovation Center of Biomedical Functional Materials, College of Chemistry and Materials Science, Nanjing Normal University, Nanjing, China
- Jiangsu Key Lab of Cancer Biomarkers, Prevention and Treatment, Collaborative Innovation Center for Personalized Cancer Medicine, Nanjing Medical University, Nanjing, China
| | - Lei Zhang
- Jiangsu Key Laboratory of Molecular and Translational Cancer Research, The Affiliated Cancer Hospital (Jiangsu Cancer Hospital), Nanjing Medical University, Nanjing, China
- Hepatobiliary Center, The First Affiliated Hospital of Nanjing Medical University & Research Unit of Liver Transplantation and Transplant Immunology, Chinese Academy of Medical Sciences, Nanjing, China
- State Key Laboratory of Reproductive Medicine, Nanjing Medical University, Nanjing, China
- Jiangsu Collaborative Innovation Center of Biomedical Functional Materials, College of Chemistry and Materials Science, Nanjing Normal University, Nanjing, China
- Jiangsu Key Lab of Cancer Biomarkers, Prevention and Treatment, Collaborative Innovation Center for Personalized Cancer Medicine, Nanjing Medical University, Nanjing, China
| | - Chengyu Shi
- Jiangsu Key Laboratory of Molecular and Translational Cancer Research, The Affiliated Cancer Hospital (Jiangsu Cancer Hospital), Nanjing Medical University, Nanjing, China
- Hepatobiliary Center, The First Affiliated Hospital of Nanjing Medical University & Research Unit of Liver Transplantation and Transplant Immunology, Chinese Academy of Medical Sciences, Nanjing, China
- State Key Laboratory of Reproductive Medicine, Nanjing Medical University, Nanjing, China
- Jiangsu Collaborative Innovation Center of Biomedical Functional Materials, College of Chemistry and Materials Science, Nanjing Normal University, Nanjing, China
- Jiangsu Key Lab of Cancer Biomarkers, Prevention and Treatment, Collaborative Innovation Center for Personalized Cancer Medicine, Nanjing Medical University, Nanjing, China
| | - Jinren Zhou
- Jiangsu Key Laboratory of Molecular and Translational Cancer Research, The Affiliated Cancer Hospital (Jiangsu Cancer Hospital), Nanjing Medical University, Nanjing, China
- Hepatobiliary Center, The First Affiliated Hospital of Nanjing Medical University & Research Unit of Liver Transplantation and Transplant Immunology, Chinese Academy of Medical Sciences, Nanjing, China
- State Key Laboratory of Reproductive Medicine, Nanjing Medical University, Nanjing, China
- Jiangsu Collaborative Innovation Center of Biomedical Functional Materials, College of Chemistry and Materials Science, Nanjing Normal University, Nanjing, China
- Jiangsu Key Lab of Cancer Biomarkers, Prevention and Treatment, Collaborative Innovation Center for Personalized Cancer Medicine, Nanjing Medical University, Nanjing, China
| | - Peng Wang
- Jiangsu Key Laboratory of Molecular and Translational Cancer Research, The Affiliated Cancer Hospital (Jiangsu Cancer Hospital), Nanjing Medical University, Nanjing, China
- Hepatobiliary Center, The First Affiliated Hospital of Nanjing Medical University & Research Unit of Liver Transplantation and Transplant Immunology, Chinese Academy of Medical Sciences, Nanjing, China
- State Key Laboratory of Reproductive Medicine, Nanjing Medical University, Nanjing, China
- Jiangsu Collaborative Innovation Center of Biomedical Functional Materials, College of Chemistry and Materials Science, Nanjing Normal University, Nanjing, China
- Jiangsu Key Lab of Cancer Biomarkers, Prevention and Treatment, Collaborative Innovation Center for Personalized Cancer Medicine, Nanjing Medical University, Nanjing, China
| | - Hao Wang
- Jiangsu Key Laboratory of Molecular and Translational Cancer Research, The Affiliated Cancer Hospital (Jiangsu Cancer Hospital), Nanjing Medical University, Nanjing, China
- Hepatobiliary Center, The First Affiliated Hospital of Nanjing Medical University & Research Unit of Liver Transplantation and Transplant Immunology, Chinese Academy of Medical Sciences, Nanjing, China
- State Key Laboratory of Reproductive Medicine, Nanjing Medical University, Nanjing, China
- Jiangsu Collaborative Innovation Center of Biomedical Functional Materials, College of Chemistry and Materials Science, Nanjing Normal University, Nanjing, China
- Jiangsu Key Lab of Cancer Biomarkers, Prevention and Treatment, Collaborative Innovation Center for Personalized Cancer Medicine, Nanjing Medical University, Nanjing, China
| | - Xiaoli Shi
- Jiangsu Key Laboratory of Molecular and Translational Cancer Research, The Affiliated Cancer Hospital (Jiangsu Cancer Hospital), Nanjing Medical University, Nanjing, China
- Hepatobiliary Center, The First Affiliated Hospital of Nanjing Medical University & Research Unit of Liver Transplantation and Transplant Immunology, Chinese Academy of Medical Sciences, Nanjing, China
- State Key Laboratory of Reproductive Medicine, Nanjing Medical University, Nanjing, China
- Jiangsu Collaborative Innovation Center of Biomedical Functional Materials, College of Chemistry and Materials Science, Nanjing Normal University, Nanjing, China
- Jiangsu Key Lab of Cancer Biomarkers, Prevention and Treatment, Collaborative Innovation Center for Personalized Cancer Medicine, Nanjing Medical University, Nanjing, China
| | - Song Wei
- Jiangsu Key Laboratory of Molecular and Translational Cancer Research, The Affiliated Cancer Hospital (Jiangsu Cancer Hospital), Nanjing Medical University, Nanjing, China
- Hepatobiliary Center, The First Affiliated Hospital of Nanjing Medical University & Research Unit of Liver Transplantation and Transplant Immunology, Chinese Academy of Medical Sciences, Nanjing, China
- State Key Laboratory of Reproductive Medicine, Nanjing Medical University, Nanjing, China
- Jiangsu Collaborative Innovation Center of Biomedical Functional Materials, College of Chemistry and Materials Science, Nanjing Normal University, Nanjing, China
- Jiangsu Key Lab of Cancer Biomarkers, Prevention and Treatment, Collaborative Innovation Center for Personalized Cancer Medicine, Nanjing Medical University, Nanjing, China
| | - Qi Wang
- Jiangsu Key Laboratory of Molecular and Translational Cancer Research, The Affiliated Cancer Hospital (Jiangsu Cancer Hospital), Nanjing Medical University, Nanjing, China
- Hepatobiliary Center, The First Affiliated Hospital of Nanjing Medical University & Research Unit of Liver Transplantation and Transplant Immunology, Chinese Academy of Medical Sciences, Nanjing, China
- State Key Laboratory of Reproductive Medicine, Nanjing Medical University, Nanjing, China
- Jiangsu Collaborative Innovation Center of Biomedical Functional Materials, College of Chemistry and Materials Science, Nanjing Normal University, Nanjing, China
- Jiangsu Key Lab of Cancer Biomarkers, Prevention and Treatment, Collaborative Innovation Center for Personalized Cancer Medicine, Nanjing Medical University, Nanjing, China
| | - Johan Auwerx
- Metabolic Signaling, School of Life Sciences, Institute of Bioengineering, Ecole Polytechnique Federale de Lausanne, Lausanne, Switzerland
| | - Kristina Schoonjans
- Metabolic Signaling, School of Life Sciences, Institute of Bioengineering, Ecole Polytechnique Federale de Lausanne, Lausanne, Switzerland
| | - Yue Yu
- Jiangsu Key Laboratory of Molecular and Translational Cancer Research, The Affiliated Cancer Hospital (Jiangsu Cancer Hospital), Nanjing Medical University, Nanjing, China
- Hepatobiliary Center, The First Affiliated Hospital of Nanjing Medical University & Research Unit of Liver Transplantation and Transplant Immunology, Chinese Academy of Medical Sciences, Nanjing, China
- State Key Laboratory of Reproductive Medicine, Nanjing Medical University, Nanjing, China
- Jiangsu Collaborative Innovation Center of Biomedical Functional Materials, College of Chemistry and Materials Science, Nanjing Normal University, Nanjing, China
- Jiangsu Key Lab of Cancer Biomarkers, Prevention and Treatment, Collaborative Innovation Center for Personalized Cancer Medicine, Nanjing Medical University, Nanjing, China
| | - Rui Pan
- Jiangsu Key Laboratory of Molecular and Translational Cancer Research, The Affiliated Cancer Hospital (Jiangsu Cancer Hospital), Nanjing Medical University, Nanjing, China
| | - Haoming Zhou
- Jiangsu Key Laboratory of Molecular and Translational Cancer Research, The Affiliated Cancer Hospital (Jiangsu Cancer Hospital), Nanjing Medical University, Nanjing, China
- Hepatobiliary Center, The First Affiliated Hospital of Nanjing Medical University & Research Unit of Liver Transplantation and Transplant Immunology, Chinese Academy of Medical Sciences, Nanjing, China
- State Key Laboratory of Reproductive Medicine, Nanjing Medical University, Nanjing, China
- Jiangsu Collaborative Innovation Center of Biomedical Functional Materials, College of Chemistry and Materials Science, Nanjing Normal University, Nanjing, China
- Jiangsu Key Lab of Cancer Biomarkers, Prevention and Treatment, Collaborative Innovation Center for Personalized Cancer Medicine, Nanjing Medical University, Nanjing, China
| | - Ling Lu
- Jiangsu Key Laboratory of Molecular and Translational Cancer Research, The Affiliated Cancer Hospital (Jiangsu Cancer Hospital), Nanjing Medical University, Nanjing, China
- Hepatobiliary Center, The First Affiliated Hospital of Nanjing Medical University & Research Unit of Liver Transplantation and Transplant Immunology, Chinese Academy of Medical Sciences, Nanjing, China
- State Key Laboratory of Reproductive Medicine, Nanjing Medical University, Nanjing, China
- Jiangsu Collaborative Innovation Center of Biomedical Functional Materials, College of Chemistry and Materials Science, Nanjing Normal University, Nanjing, China
- Jiangsu Key Lab of Cancer Biomarkers, Prevention and Treatment, Collaborative Innovation Center for Personalized Cancer Medicine, Nanjing Medical University, Nanjing, China
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Li X, Wang J, Gong X, Zhang M, Kang S, Shu B, Wei Z, Huang ZS, Li D. Upregulation of BCL-2 by acridone derivative through gene promoter i-motif for alleviating liver damage of NAFLD/NASH. Nucleic Acids Res 2020; 48:8255-8268. [PMID: 32710621 PMCID: PMC7470982 DOI: 10.1093/nar/gkaa615] [Citation(s) in RCA: 20] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/22/2020] [Revised: 06/29/2020] [Accepted: 07/11/2020] [Indexed: 12/15/2022] Open
Abstract
Nonalcoholic fatty liver disease (NAFLD)/nonalcoholic steatohepatitis (NASH) are global epidemic public health problems with pathogenesis incompletely understood. Hepatocyte excessive apoptosis is a significant symbol for NAFLD/NASH patients, and therefore anti-apoptosis therapy could be used for NAFLD/NASH treatment. Up-regulation of BCL-2 has been found to be closely related with anti-apoptosis. BCL-2 gene promoter region has a C-rich sequence, which can form i-motif structure and play important role in regulating gene transcription. In this study, after extensive screening and evaluation, we found that acridone derivative A22 could up-regulate BCL-2 transcription and translation in vitro and in cells through selective binding to and stabilizing BCL-2 gene promoter i-motif. Our further experiments showed that A22 could reduce hepatocyte apoptosis in NAFLD/NASH model possibly through up-regulating BCL-2 expression. A22 could reduce inflammation, endoplasmic reticulum stress and cirrhosis in high-fat diet-fed mice liver model. Our findings provide a potentially new approach of anti-apoptosis for NAFLD/NASH treatment, and A22 could be further developed as a lead compound for NAFLD/NASH therapy. Our present study first demonstrated that gene promoter i-motif could be targeted for gene up-regulation for extended treatment of other important diseases besides cancer.
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Affiliation(s)
- Xiaoya Li
- School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou University City, 132 Wai huan East Road, Guangzhou 510006, P. R. China
| | - Jing Wang
- School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou University City, 132 Wai huan East Road, Guangzhou 510006, P. R. China
| | - Xue Gong
- School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou University City, 132 Wai huan East Road, Guangzhou 510006, P. R. China
| | - Meiling Zhang
- School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou University City, 132 Wai huan East Road, Guangzhou 510006, P. R. China
| | - Shuangshuang Kang
- School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou University City, 132 Wai huan East Road, Guangzhou 510006, P. R. China
| | - Bing Shu
- School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou University City, 132 Wai huan East Road, Guangzhou 510006, P. R. China
| | - Zuzhuang Wei
- School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou University City, 132 Wai huan East Road, Guangzhou 510006, P. R. China
| | - Zhi-Shu Huang
- School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou University City, 132 Wai huan East Road, Guangzhou 510006, P. R. China
| | - Ding Li
- School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou University City, 132 Wai huan East Road, Guangzhou 510006, P. R. China
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Relative contribution of fat diet and physical inactivity to the development of metabolic syndrome and non-alcoholic fat liver disease in Wistar rats. Physiol Behav 2020; 225:113040. [PMID: 32603747 DOI: 10.1016/j.physbeh.2020.113040] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/06/2020] [Revised: 06/24/2020] [Accepted: 06/26/2020] [Indexed: 01/22/2023]
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Ramachandran P, Matchett KP, Dobie R, Wilson-Kanamori JR, Henderson NC. Single-cell technologies in hepatology: new insights into liver biology and disease pathogenesis. Nat Rev Gastroenterol Hepatol 2020; 17:457-472. [PMID: 32483353 DOI: 10.1038/s41575-020-0304-x] [Citation(s) in RCA: 161] [Impact Index Per Article: 32.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 04/08/2020] [Indexed: 12/19/2022]
Abstract
Liver disease is a major global health-care problem, affecting an estimated 844 million people worldwide. Despite this substantial burden, therapeutic options for liver disease remain limited, in part owing to a paucity of detailed analyses defining the cellular and molecular mechanisms that drive these conditions in humans. Single-cell transcriptomic technologies are transforming our understanding of cellular diversity and function in health and disease. In this Review, we discuss how these technologies have been applied in hepatology, advancing our understanding of cellular heterogeneity and providing novel insights into fundamental liver biology such as the metabolic zonation of hepatocytes, endothelial cells and hepatic stellate cells, and the cellular mechanisms underpinning liver regeneration. Application of these methodologies is also uncovering critical pathophysiological changes driving disease states such as hepatic fibrosis, where distinct populations of macrophages, endothelial cells and mesenchymal cells reside within a spatially distinct fibrotic niche and interact to promote scar formation. In addition, single-cell approaches are starting to dissect key cellular and molecular functions in liver cancer. In the near future, new techniques such as spatial transcriptomics and multiomic approaches will further deepen our understanding of disease pathogenesis, enabling the identification of novel therapeutic targets for patients across the spectrum of liver diseases.
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Affiliation(s)
- Prakash Ramachandran
- Centre for Inflammation Research, The Queen's Medical Research Institute, University of Edinburgh, Edinburgh, UK
| | - Kylie P Matchett
- Centre for Inflammation Research, The Queen's Medical Research Institute, University of Edinburgh, Edinburgh, UK
| | - Ross Dobie
- Centre for Inflammation Research, The Queen's Medical Research Institute, University of Edinburgh, Edinburgh, UK
| | - John R Wilson-Kanamori
- Centre for Inflammation Research, The Queen's Medical Research Institute, University of Edinburgh, Edinburgh, UK
| | - Neil C Henderson
- Centre for Inflammation Research, The Queen's Medical Research Institute, University of Edinburgh, Edinburgh, UK. .,MRC Human Genetics Unit, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, UK.
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Liu B, Deng X, Jiang Q, Li G, Zhang J, Zhang N, Xin S, Xu K. Scoparone alleviates inflammation, apoptosis and fibrosis of non-alcoholic steatohepatitis by suppressing the TLR4/NF-κB signaling pathway in mice. Int Immunopharmacol 2019; 75:105797. [DOI: 10.1016/j.intimp.2019.105797] [Citation(s) in RCA: 34] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/25/2019] [Revised: 07/10/2019] [Accepted: 07/31/2019] [Indexed: 12/24/2022]
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Ezzaidi N, Zhang X, Coker OO, Yu J. New insights and therapeutic implication of gut microbiota in non-alcoholic fatty liver disease and its associated liver cancer. Cancer Lett 2019; 459:186-191. [PMID: 31185249 DOI: 10.1016/j.canlet.2019.114425] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2019] [Revised: 05/21/2019] [Accepted: 06/04/2019] [Indexed: 02/09/2023]
Abstract
The gastrointestinal tract represents one of the largest interfaces between the host and environmental factors. It contains a vast and complex community of microbes, forming what is collectively known as the microbiota. This gut microbiota plays a pivotal role in the maintenance of health, and 'dysbiosis' of the gut microbiota, commonly considered as perturbation of microbiota diversity and composition, has been associated with intestinal and extra-intestinal diseases, including non-alcoholic fatty liver disease (NAFLD) and its associated hepatocellular carcinoma (NAFLD-HCC). In this review, we highlight microbiota dysbiosis and the microbiota-host interactions that link to the pathogenesis of NAFLD and NAFLD-HCC. We discuss the potential therapeutic implications of the gut microbiota in the progression of NAFLD-HCC.
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Affiliation(s)
- Niama Ezzaidi
- Institute of Digestive Disease and the Department of Medicine and Therapeutics, State Key Laboratory of Digestive Disease, The Chinese University of Hong Kong, Hong Kong; MChem Chemistry and Drug Discovery, University of Sussex, UK
| | - Xiang Zhang
- Institute of Digestive Disease and the Department of Medicine and Therapeutics, State Key Laboratory of Digestive Disease, The Chinese University of Hong Kong, Hong Kong
| | - Olabisi Oluwabukola Coker
- Institute of Digestive Disease and the Department of Medicine and Therapeutics, State Key Laboratory of Digestive Disease, The Chinese University of Hong Kong, Hong Kong
| | - Jun Yu
- Institute of Digestive Disease and the Department of Medicine and Therapeutics, State Key Laboratory of Digestive Disease, The Chinese University of Hong Kong, Hong Kong.
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Abu-Elsaad N, El-Karef A. Protection against nonalcoholic steatohepatitis through targeting IL-18 and IL-1alpha by luteolin. Pharmacol Rep 2019; 71:688-694. [PMID: 31207429 DOI: 10.1016/j.pharep.2019.03.009] [Citation(s) in RCA: 30] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/06/2018] [Revised: 02/02/2019] [Accepted: 03/14/2019] [Indexed: 02/07/2023]
Abstract
BACKGROUND The management of nonalcoholic steatohepatitis (NASH) is still a crosstalk so the current study was designed to evaluate the effect of different luteolin doses on an experimental model of NASH and to elucidate novel anti-inflammatory pathways underlying its effect. METHODS Adult male Wistar rats (200-220 g; n = 60) were used. Rats were fed a high carbohydrate/high fat diet (˜ 30% carbohydrate and 42% fat) daily for 12 weeks to induce NASH. Luteolin (10, 25, 50 or 100 mg/kg/day) was administered as a suspension (10% w/v in 0.9% NaCl) using an oral gavage. Histopathological changes (necrosis, inflammation and steatosis) were evaluated. Biomarkers for liver function, lipid peroxidation, extracellular matrix deposition and anti-oxidant activity were measured. Levels of IFN-γ, TNF-α and IL-1α and IL-18 were measured. RESULTS Obtained results showed ability of luteolin to reduce activity of ALT and AST and to decrease levels of bilirubin, hyaluronic acid and malondialdehyde significantly (p < 0.05). Also, luteolin showed an anti-oxidant activity as indicated by the significant (p < 0.05) increase in reduced glutathione. Finally, a significant (p < 0.05) decrease in IFN-γ, TNF-α, IL-1α and IL-18 levels was observed most notably in groups that received high doses of luteolin (50 and 100 mg/kg). CONCLUSIONS Luteolin can protect against non-alcoholic steatohepatitis through targeting the pro-inflammatory IL-1 and Il-18 pathways in addition to an antioxidant effect.
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Affiliation(s)
- Nashwa Abu-Elsaad
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Mansoura, Egypt.
| | - Amr El-Karef
- Department of Pathology, Faculty of Medicine, Mansoura University, Mansoura, Egypt.
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Jiang M, Wu N, Chen X, Wang W, Chu Y, Liu H, Li W, Chen D, Li X, Xu B. Pathogenesis of and major animal models used for nonalcoholic fatty liver disease. J Int Med Res 2019; 47:1453-1466. [PMID: 30871397 PMCID: PMC6460620 DOI: 10.1177/0300060519833527] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/27/2022] Open
Abstract
Nonalcoholic fatty liver disease (NAFLD) and its pathologically more severe form, nonalcoholic steatohepatitis (NASH), have become prevalent worldwide and carry an increased risk of developing hepatocellular carcinoma and other metabolic diseases. Diverse animal models have been proposed to replicate particular characteristics of NAFLD and NASH and have provided significant clues to the critical molecular targets of NASH treatment. In this review, we summarize the histopathology, pathogenesis, and molecular basis of NAFLD progression and discuss the benchmark animal models of NAFLD/NASH.
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Affiliation(s)
- Mingzuo Jiang
- 1 State Key Laboratory of Cancer Biology & Institute of Digestive Diseases, Xijing Hospital, The Air-Force Military Medical University, Xi'an, Shaanxi, China
| | - Nan Wu
- 2 Laboratory of Tissue Engineering, Faculty of Life Science, Northwest University, Xi'an, Shaanxi, China
| | - Xi Chen
- 3 Department of Surgical Anesthesiology, Shaanxi Provincial Hospital of Traditional Chinese Medicine, Xi'an, Shaanxi, China
| | - Weijie Wang
- 1 State Key Laboratory of Cancer Biology & Institute of Digestive Diseases, Xijing Hospital, The Air-Force Military Medical University, Xi'an, Shaanxi, China
| | - Yi Chu
- 1 State Key Laboratory of Cancer Biology & Institute of Digestive Diseases, Xijing Hospital, The Air-Force Military Medical University, Xi'an, Shaanxi, China
| | - Hao Liu
- 1 State Key Laboratory of Cancer Biology & Institute of Digestive Diseases, Xijing Hospital, The Air-Force Military Medical University, Xi'an, Shaanxi, China
| | - Wenjiao Li
- 1 State Key Laboratory of Cancer Biology & Institute of Digestive Diseases, Xijing Hospital, The Air-Force Military Medical University, Xi'an, Shaanxi, China
| | - Di Chen
- 1 State Key Laboratory of Cancer Biology & Institute of Digestive Diseases, Xijing Hospital, The Air-Force Military Medical University, Xi'an, Shaanxi, China.,5 Department of Gastroenterology, Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi, China
| | - Xiaowei Li
- 4 Department of Gastroenterology, PLA Navy General Hospital, Beijing, China.,5 Department of Gastroenterology, Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi, China
| | - Bing Xu
- 5 Department of Gastroenterology, Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi, China
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Abstract
Non-alcoholic fatty liver disease (NAFLD) is an increasingly important cause of chronic liver disease globally. Similar to metabolic syndrome and obesity, NAFLD is associated with alternations in the gut microbiota and its related biological pathways. While the exact pathophysiology of NAFLD remains largely unknown, changes in intestinal inflammation, gut permeability, energy harvest, anaerobic fermentation and insulin resistance have been described. In this chapter, we review the relationship between the gut microbiota, obesity and NAFLD, and highlight potential ways to modify the gut microbiota to help managing NAFLD patients.
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Affiliation(s)
- Louis H S Lau
- Institute of Digestive Disease, State Key Laboratory of Digestive Diseases, Department of Medicine & Therapeutics and LKS Institute of Health Sciences, The Chinese University of Hong Kong, Hong Kong, Hong Kong
| | - Sunny H Wong
- Institute of Digestive Disease, State Key Laboratory of Digestive Diseases, Department of Medicine & Therapeutics and LKS Institute of Health Sciences, The Chinese University of Hong Kong, Hong Kong, Hong Kong.
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19
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Kanda T, Matsuoka S, Yamazaki M, Shibata T, Nirei K, Takahashi H, Kaneko T, Fujisawa M, Higuchi T, Nakamura H, Matsumoto N, Yamagami H, Ogawa M, Imazu H, Kuroda K, Moriyama M. Apoptosis and non-alcoholic fatty liver diseases. World J Gastroenterol 2018; 24:2661-2672. [PMID: 29991872 PMCID: PMC6034146 DOI: 10.3748/wjg.v24.i25.2661] [Citation(s) in RCA: 210] [Impact Index Per Article: 30.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/02/2018] [Revised: 06/04/2018] [Accepted: 06/21/2018] [Indexed: 02/06/2023] Open
Abstract
The number of patients with nonalcoholic fatty liver diseases (NAFLD) including nonalcoholic steatohepatitis (NASH), has been increasing. NASH causes cirrhosis and hepatocellular carcinoma (HCC) and is one of the most serious health problems in the world. The mechanism through which NASH progresses is still largely unknown. Activation of caspases, Bcl-2 family proteins, and c-Jun N-terminal kinase-induced hepatocyte apoptosis plays a role in the activation of NAFLD/NASH. Apoptotic hepatocytes stimulate immune cells and hepatic stellate cells toward the progression of fibrosis in the liver through the production of inflammasomes and cytokines. Abnormalities in glucose and lipid metabolism as well as microbiota accelerate these processes. The production of reactive oxygen species, oxidative stress, and endoplasmic reticulum stress is also involved. Cell death, including apoptosis, seems very important in the progression of NAFLD and NASH. Recently, inhibitors of apoptosis have been developed as drugs for the treatment of NASH and may prevent cirrhosis and HCC. Increased hepatocyte apoptosis may distinguish NASH from NAFLD, and the improvement of apoptosis could play a role in controlling the development of NASH. In this review, the association between apoptosis and NAFLD/NASH are discussed. This review could provide their knowledge, which plays a role in seeing the patients with NAFLD/NASH in daily clinical practice.
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Affiliation(s)
- Tatsuo Kanda
- Division of Gastroenterology and Hepatology, Department of Medicine, Nihon University School of Medicine, Itabashi-ku, Tokyo 173-8610, Japan
| | - Shunichi Matsuoka
- Division of Gastroenterology and Hepatology, Department of Medicine, Nihon University School of Medicine, Itabashi-ku, Tokyo 173-8610, Japan
| | - Motomi Yamazaki
- Division of Gastroenterology and Hepatology, Department of Medicine, Nihon University School of Medicine, Itabashi-ku, Tokyo 173-8610, Japan
| | - Toshikatsu Shibata
- Division of Gastroenterology and Hepatology, Department of Medicine, Nihon University School of Medicine, Itabashi-ku, Tokyo 173-8610, Japan
| | - Kazushige Nirei
- Division of Gastroenterology and Hepatology, Department of Medicine, Nihon University School of Medicine, Itabashi-ku, Tokyo 173-8610, Japan
| | - Hiroshi Takahashi
- Division of Gastroenterology and Hepatology, Department of Medicine, Nihon University School of Medicine, Itabashi-ku, Tokyo 173-8610, Japan
| | - Tomohiro Kaneko
- Division of Gastroenterology and Hepatology, Department of Medicine, Nihon University School of Medicine, Itabashi-ku, Tokyo 173-8610, Japan
| | - Mariko Fujisawa
- Division of Gastroenterology and Hepatology, Department of Medicine, Nihon University School of Medicine, Itabashi-ku, Tokyo 173-8610, Japan
| | - Teruhisa Higuchi
- Division of Gastroenterology and Hepatology, Department of Medicine, Nihon University School of Medicine, Itabashi-ku, Tokyo 173-8610, Japan
| | - Hitomi Nakamura
- Division of Gastroenterology and Hepatology, Department of Medicine, Nihon University School of Medicine, Itabashi-ku, Tokyo 173-8610, Japan
| | - Naoki Matsumoto
- Division of Gastroenterology and Hepatology, Department of Medicine, Nihon University School of Medicine, Itabashi-ku, Tokyo 173-8610, Japan
| | - Hiroaki Yamagami
- Division of Gastroenterology and Hepatology, Department of Medicine, Nihon University School of Medicine, Itabashi-ku, Tokyo 173-8610, Japan
| | - Masahiro Ogawa
- Division of Gastroenterology and Hepatology, Department of Medicine, Nihon University School of Medicine, Itabashi-ku, Tokyo 173-8610, Japan
| | - Hiroo Imazu
- Division of Gastroenterology and Hepatology, Department of Medicine, Nihon University School of Medicine, Itabashi-ku, Tokyo 173-8610, Japan
| | - Kazumichi Kuroda
- Division of Gastroenterology and Hepatology, Department of Medicine, Nihon University School of Medicine, Itabashi-ku, Tokyo 173-8610, Japan
| | - Mitsuhiko Moriyama
- Division of Gastroenterology and Hepatology, Department of Medicine, Nihon University School of Medicine, Itabashi-ku, Tokyo 173-8610, Japan
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20
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Rein-Fischboeck L, Haberl EM, Pohl R, Schmid V, Feder S, Krautbauer S, Liebisch G, Buechler C. Alpha-syntrophin null mice are protected from non-alcoholic steatohepatitis in the methionine-choline-deficient diet model but not the atherogenic diet model. Biochim Biophys Acta Mol Cell Biol Lipids 2018; 1863:526-537. [PMID: 29474931 DOI: 10.1016/j.bbalip.2018.02.006] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/22/2017] [Revised: 01/23/2018] [Accepted: 02/17/2018] [Indexed: 12/13/2022]
Abstract
Adipose tissue dysfunction contributes to the pathogenesis of non-alcoholic steatohepatitis (NASH). The adapter protein alpha-syntrophin (SNTA) is expressed in adipocytes. Knock-down of SNTA increases preadipocyte proliferation and formation of small lipid droplets, which are both characteristics of healthy adipose tissue. To elucidate a potential protective role of SNTA in NASH, SNTA null mice were fed a methionine-choline-deficient (MCD) diet or an atherogenic diet which are widely used as preclinical NASH models. MCD diet mediated loss of fat mass was largely improved in SNTA-/- mice compared to the respective wild type animals. Hepatic lipids were mostly unchanged while the oxidative stress marker malondialdehyde was only induced in the wild type mice. The expression of inflammatory markers and macrophage immigration into the liver were reduced in SNTA-/- animals. This protective function of SNTA loss was absent in atherogenic diet induced NASH. Here, hepatic expression of inflammatory and fibrotic genes was similar in both genotypes though mutant mice gained less body fat during feeding. Hepatic cholesterol and ceramide were strongly induced in both strains upon feeding the atherogenic diet, while hepatic sphingomyelin, phosphatidylserine and phosphatidylethanolamine levels were suppressed. SNTA deficient mice are protected from fat loss and NASH in the experimental MCD model. NASH induced by an atherogenic diet is not influenced by loss of SNTA. The present study suggests the use of different experimental NASH models to study the pathophysiological role of proteins like SNTA in NASH.
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Affiliation(s)
- Lisa Rein-Fischboeck
- Department of Internal Medicine I, Regensburg University Hospital, Regensburg, Germany
| | - Elisabeth M Haberl
- Department of Internal Medicine I, Regensburg University Hospital, Regensburg, Germany
| | - Rebekka Pohl
- Department of Internal Medicine I, Regensburg University Hospital, Regensburg, Germany
| | - Verena Schmid
- Department of Internal Medicine I, Regensburg University Hospital, Regensburg, Germany
| | - Susanne Feder
- Department of Internal Medicine I, Regensburg University Hospital, Regensburg, Germany
| | - Sabrina Krautbauer
- Institute of Clinical Chemistry and Laboratory Medicine, Regensburg University Hospital, Regensburg, Germany
| | - Gerhard Liebisch
- Institute of Clinical Chemistry and Laboratory Medicine, Regensburg University Hospital, Regensburg, Germany
| | - Christa Buechler
- Department of Internal Medicine I, Regensburg University Hospital, Regensburg, Germany.
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21
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Abstract
Macrophages represent a key cellular component of the liver, and are essential for maintaining tissue homeostasis and ensuring rapid responses to hepatic injury. Our understanding of liver macrophages has been revolutionized by the delineation of heterogeneous subsets of these cells. Kupffer cells are a self-sustaining, liver-resident population of macrophages and can be distinguished from the monocyte-derived macrophages that rapidly accumulate in the injured liver. Specific environmental signals further determine the polarization and function of hepatic macrophages. These cells promote the restoration of tissue integrity following liver injury or infection, but they can also contribute to the progression of liver diseases, including hepatitis, fibrosis and cancer. In this Review, we highlight novel findings regarding the origin, classification and function of hepatic macrophages, and we discuss their divergent roles in the healthy and diseased liver.
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Affiliation(s)
- Oliver Krenkel
- Department of Medicine III, University Hospital Aachen, D-52074 Aachen, Germany
| | - Frank Tacke
- Department of Medicine III, University Hospital Aachen, D-52074 Aachen, Germany
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22
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Wong VWS, Chitturi S, Wong GLH, Yu J, Chan HLY, Farrell GC. Pathogenesis and novel treatment options for non-alcoholic steatohepatitis. Lancet Gastroenterol Hepatol 2016; 1:56-67. [PMID: 28404113 DOI: 10.1016/s2468-1253(16)30011-5] [Citation(s) in RCA: 141] [Impact Index Per Article: 15.7] [Reference Citation Analysis] [Abstract] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/05/2016] [Revised: 05/12/2016] [Accepted: 05/13/2016] [Indexed: 02/06/2023]
Abstract
Non-alcoholic fatty liver disease affects 20-40% of the population. Its active form, non-alcoholic steatohepatitis (NASH), is characterised by hepatocyte injury, liver inflammation, and progression of fibrosis, and has emerged as one of the most important causes of liver failure and hepatocellular carcinoma. Weight reduction of 10% by dietary restriction and regular exercise is sufficient to reverse NASH in most patients, but in practice this reduction is often not achieved. Available drugs such as vitamin E, pioglitazone, and pentoxifylline have borderline efficacy, but are limited by potential side-effects and toxicities, and do not improve liver fibrosis. However, basic and translational research has improved our understanding of the pathophysiology of NASH, thereby identifying several promising new treatment targets. Several drugs are in phase 2 and 3 development and could enter clinical practice in the near future. In this Review, we discuss the pathogenesis, treatment evaluation, existing therapies, and potential new treatments for NASH.
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Affiliation(s)
- Vincent Wai-Sun Wong
- Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Hong Kong SAR, China; State Key Laboratory of Digestive Disease, The Chinese University of Hong Kong, Hong Kong SAR, China.
| | - Shiv Chitturi
- Liver Research Group, Australian National University Medical School at The Canberra Hospital, Woden, ACT, Australia
| | - Grace Lai-Hung Wong
- Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Hong Kong SAR, China; State Key Laboratory of Digestive Disease, The Chinese University of Hong Kong, Hong Kong SAR, China
| | - Jun Yu
- Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Hong Kong SAR, China; State Key Laboratory of Digestive Disease, The Chinese University of Hong Kong, Hong Kong SAR, China
| | - Henry Lik-Yuen Chan
- Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Hong Kong SAR, China; State Key Laboratory of Digestive Disease, The Chinese University of Hong Kong, Hong Kong SAR, China
| | - Geoffrey C Farrell
- Liver Research Group, Australian National University Medical School at The Canberra Hospital, Woden, ACT, Australia
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