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Boulos M, Mousa RS, Jeries N, Simaan E, Alam K, Bulus B, Assy N. Hidden in the Fat: Unpacking the Metabolic Tango Between Metabolic Dysfunction-Associated Steatotic Liver Disease and Metabolic Syndrome. Int J Mol Sci 2025; 26:3448. [PMID: 40244398 PMCID: PMC11989262 DOI: 10.3390/ijms26073448] [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: 02/07/2025] [Revised: 03/25/2025] [Accepted: 03/30/2025] [Indexed: 04/18/2025] Open
Abstract
Metabolic syndrome (MetS) and metabolic dysfunction-associated steatotic liver disease (MASLD) are closely related, with rapidly increasing prevalence globally, driving significant public health concerns. Both conditions share common pathophysiological mechanisms such as insulin resistance (IR), adipose tissue dysfunction, oxidative stress, and gut microbiota dysbiosis, which contribute to their co-occurrence and progression. While the clinical implications of this overlap, including increased cardiovascular, renal, and hepatic risk, are well recognized, current diagnostic and therapeutic approaches remain insufficient due to the clinical and individuals' heterogeneity and complexity of these diseases. This review aims to provide an in-depth exploration of the molecular mechanisms linking MetS and MASLD, identify critical gaps in our understanding, and highlight existing challenges in early detection and treatment. Despite advancements in biomarkers and therapeutic interventions, the need for a comprehensive, integrated approach remains. The review also discusses emerging therapies targeting specific pathways, the potential of precision medicine, and the growing role of artificial intelligence in enhancing research and clinical management. Future research is urgently needed to combine multi-omics data, precision medicine, and novel biomarkers to better understand the complex interactions between MetS and MASLD. Collaborative, multidisciplinary efforts are essential to develop more effective diagnostic tools and therapies to address these diseases on a global scale.
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Affiliation(s)
- Mariana Boulos
- Internal Medicine Department, Galilee Medical Centre, Nahariya 221001, Israel; (R.S.M.); (N.J.); (E.S.); (K.A.); (B.B.); (N.A.)
- The Azrieli Faculty of Medicine, Bar-Ilan University, Safed 1311502, Israel
| | - Rabia S. Mousa
- Internal Medicine Department, Galilee Medical Centre, Nahariya 221001, Israel; (R.S.M.); (N.J.); (E.S.); (K.A.); (B.B.); (N.A.)
| | - Nizar Jeries
- Internal Medicine Department, Galilee Medical Centre, Nahariya 221001, Israel; (R.S.M.); (N.J.); (E.S.); (K.A.); (B.B.); (N.A.)
| | - Elias Simaan
- Internal Medicine Department, Galilee Medical Centre, Nahariya 221001, Israel; (R.S.M.); (N.J.); (E.S.); (K.A.); (B.B.); (N.A.)
| | - Klode Alam
- Internal Medicine Department, Galilee Medical Centre, Nahariya 221001, Israel; (R.S.M.); (N.J.); (E.S.); (K.A.); (B.B.); (N.A.)
| | - Bulus Bulus
- Internal Medicine Department, Galilee Medical Centre, Nahariya 221001, Israel; (R.S.M.); (N.J.); (E.S.); (K.A.); (B.B.); (N.A.)
| | - Nimer Assy
- Internal Medicine Department, Galilee Medical Centre, Nahariya 221001, Israel; (R.S.M.); (N.J.); (E.S.); (K.A.); (B.B.); (N.A.)
- The Azrieli Faculty of Medicine, Bar-Ilan University, Safed 1311502, Israel
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Pennisi G, Di Maria G, Enea M, Vaccaro M, Celsa C, Antonucci M, Ciancimino G, Ciccioli C, Infantino G, La Mantia C, Tulone A, Di Marco V, Cammà C, Petta S. A Markov Model Unveiling the Impact of Resmetirom on the Natural History of MASLD Patients: A Sistematic Review and Meta-Analysis. Liver Int 2025; 45:e70056. [PMID: 40066918 PMCID: PMC11894919 DOI: 10.1111/liv.70056] [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: 12/13/2024] [Revised: 02/07/2025] [Accepted: 02/23/2025] [Indexed: 03/15/2025]
Abstract
BACKGROUND AND AIM The MAESTRO-NASH phase 3 trial reported that a 52-week treatment of Resmetirom is effective in improving fibrosis and metabolic dysfunction-associated steatohepatitis (MASH) in patients with MASH and F2 or F3 fibrosis, while data on the impact on 5-year and long-term clinical outcomes are still lacking. We simulated the transition probabilities of disease progression in MASLD patients with F2 or F3 fibrosis and the effect of Resmetirom treatment on clinical outcomes. METHODS A meta-analysis of literature data formed transition matrices for fibrosis stages and complications, defined as compensated (CC) and decompensated cirrhosis (DC), hepatocellular carcinoma (HCC) and mortality-liver-related mortality (LR-M), cardiovascular mortality (CV-M) and extra-hepatic cancer mortality (EHC-M). Markov model was developed to depict the F2 and F3 fibrosis stage progression towards the complications and to evaluate the effect of Resmetirom treatment on the natural history of MASLD. RESULTS We estimated the 5-year probability of Resmetirom-treated and untreated MASLD patients with baseline F2 fibrosis of developing CC (5.16% vs. 6.82%, respectively), DC (0.25% vs. 0.3%, respectively), HCC (0.25% vs. 0.32%, respectively) and mortality (0.15% vs. 0.16% for LR-M; 1.02% vs. 1.1% for CV-M; 1.07% vs. 1.2% for EHC-M, respectively). Similarly, we estimated the five-year probability of Resmetirom-treated and untreated MASLD patients with baseline F3 fibrosis of developing CC (17.12% vs. 21.34%, respectively), DC(1.1% vs. 1.47%, respectively), HCC (1.21% vs. 1.73%, respectively) and mortality (0.59% vs. 0.91% for LR-M, 1.92% vs. 2.14% for CV-M and 1.04% vs. 1.14% for EHC-M, respectively). Life Years Gained (LYG) of Resmetirom-treated patients were 0.45 and 0.63 in MASLD patients with F2 and F3 fibrosis, respectively, and the model was sensitive to changes in Resmetirom efficacy and transition probabilities. CONCLUSIONS Resmetirom decreases the 5-year and lifetime Markov-model estimated risk of CC, DC, HCC and liver-related mortality in patients with MASLD and F2 or F3 fibrosis.
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Affiliation(s)
- Grazia Pennisi
- Section of Gastroenterology and Hepatology, Department of Health Promotion, Maternal and Child Health, Internal and Specialty Medicine of Excellence (PROMISE)University of PalermoPalermoItaly
| | - Gabriele Di Maria
- Department of Health Promotion, Maternal and Child Health, Internal and Specialty Medicine of Excellence (PROMISE)University of PalermoPalermoItaly
| | - Marco Enea
- Department of Health Promotion, Maternal and Child Health, Internal and Specialty Medicine of Excellence (PROMISE)University of PalermoPalermoItaly
| | - Marco Vaccaro
- Department of Economic, Business, and Statistical SciencesUniversity of PalermoPalermoItaly
| | - Ciro Celsa
- Section of Gastroenterology and Hepatology, Department of Health Promotion, Maternal and Child Health, Internal and Specialty Medicine of Excellence (PROMISE)University of PalermoPalermoItaly
| | - Michela Antonucci
- Department of Biomedicine, Neurosciences, and Advanced Diagnostics (BIND)University of PalermoPalermoItaly
| | - Giacinta Ciancimino
- Section of Gastroenterology and Hepatology, Department of Health Promotion, Maternal and Child Health, Internal and Specialty Medicine of Excellence (PROMISE)University of PalermoPalermoItaly
| | - Carlo Ciccioli
- Section of Gastroenterology and Hepatology, Department of Health Promotion, Maternal and Child Health, Internal and Specialty Medicine of Excellence (PROMISE)University of PalermoPalermoItaly
| | - Giuseppe Infantino
- Section of Gastroenterology and Hepatology, Department of Health Promotion, Maternal and Child Health, Internal and Specialty Medicine of Excellence (PROMISE)University of PalermoPalermoItaly
| | - Claudia La Mantia
- Section of Gastroenterology and Hepatology, Department of Health Promotion, Maternal and Child Health, Internal and Specialty Medicine of Excellence (PROMISE)University of PalermoPalermoItaly
| | - Adele Tulone
- Section of Gastroenterology and Hepatology, Department of Health Promotion, Maternal and Child Health, Internal and Specialty Medicine of Excellence (PROMISE)University of PalermoPalermoItaly
| | - Vito Di Marco
- Section of Gastroenterology and Hepatology, Department of Health Promotion, Maternal and Child Health, Internal and Specialty Medicine of Excellence (PROMISE)University of PalermoPalermoItaly
| | - Calogero Cammà
- Section of Gastroenterology and Hepatology, Department of Health Promotion, Maternal and Child Health, Internal and Specialty Medicine of Excellence (PROMISE)University of PalermoPalermoItaly
| | - Salvatore Petta
- Section of Gastroenterology and Hepatology, Department of Health Promotion, Maternal and Child Health, Internal and Specialty Medicine of Excellence (PROMISE)University of PalermoPalermoItaly
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Chen B, Guan L, Wu C, Gong Y, Wu L, Zhang M, Cao Z, Chen Y, Yang C, Wang B, Li Y, Li B, Bi Y, Ning G, Wang J, Wang W, Liu R. Gut Microbiota-Butyrate-PPARγ Axis Modulates Adipose Regulatory T Cell Population. ADVANCED SCIENCE (WEINHEIM, BADEN-WURTTEMBERG, GERMANY) 2025:e2411086. [PMID: 39998325 DOI: 10.1002/advs.202411086] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/12/2024] [Revised: 01/18/2025] [Indexed: 02/26/2025]
Abstract
Gut microbiota is essential for the function of peripherally-induced regulatory T (pTreg) cells. However, how commensal bacteria affect thymically derived fat-resident Treg cells that harbor a unique expression of peroxisome proliferator-activated receptor (PPAR)-γ and suppress inflammation in visceral adipose tissue (VAT), is not well defined. Here it is revealed that microbiota depletion causes a drastic decline in Treg cell population in VAT, particularly those expressing ST2 (ST2+ Treg), which are largely restored after gut microbiome reconstruction. Mechanistically, gut microbiota-derived butyrate increases VAT ST2+ Treg cells through binding PPARγ. Butyrate supplementation and high fiber diet increase VAT ST2+ Treg population in obese mice, and ameliorated glucose tolerance and visceral inflammation. Furthermore, human omental adipose Treg cells show positive correlation with fecal butyrate and certain butyrate-producing microbes. This study identifies the critical role of gut microbiota-butyrate-PPARγ axis in maintaining VAT Treg population, pinpointing a potential approach to augment VAT Treg population and ameliorate inflammation.
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Affiliation(s)
- Banru Chen
- Department of Endocrine and Metabolic Diseases, Shanghai Institute of Endocrine and Metabolic Diseases, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China
- Shanghai National Clinical Research Center for Metabolic Diseases, Key Laboratory for Endocrine and Metabolic Diseases of the National Health Commission of the PR China, Shanghai Key Laboratory for Endocrine Tumor, State Key Laboratory of Medical Genomics, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China
| | - Lizhi Guan
- Department of Endocrine and Metabolic Diseases, Shanghai Institute of Endocrine and Metabolic Diseases, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China
- Shanghai National Clinical Research Center for Metabolic Diseases, Key Laboratory for Endocrine and Metabolic Diseases of the National Health Commission of the PR China, Shanghai Key Laboratory for Endocrine Tumor, State Key Laboratory of Medical Genomics, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China
| | - Chao Wu
- Department of Endocrine and Metabolic Diseases, Shanghai Institute of Endocrine and Metabolic Diseases, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China
- Shanghai National Clinical Research Center for Metabolic Diseases, Key Laboratory for Endocrine and Metabolic Diseases of the National Health Commission of the PR China, Shanghai Key Laboratory for Endocrine Tumor, State Key Laboratory of Medical Genomics, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China
| | - Yiwen Gong
- Department of Endocrine and Metabolic Diseases, Shanghai Institute of Endocrine and Metabolic Diseases, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China
- Shanghai National Clinical Research Center for Metabolic Diseases, Key Laboratory for Endocrine and Metabolic Diseases of the National Health Commission of the PR China, Shanghai Key Laboratory for Endocrine Tumor, State Key Laboratory of Medical Genomics, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China
| | - Lei Wu
- Department of Endocrine and Metabolic Diseases, Shanghai Institute of Endocrine and Metabolic Diseases, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China
- Shanghai National Clinical Research Center for Metabolic Diseases, Key Laboratory for Endocrine and Metabolic Diseases of the National Health Commission of the PR China, Shanghai Key Laboratory for Endocrine Tumor, State Key Laboratory of Medical Genomics, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China
| | - Minchun Zhang
- Department of Endocrine and Metabolic Diseases, Shanghai Institute of Endocrine and Metabolic Diseases, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China
- Shanghai National Clinical Research Center for Metabolic Diseases, Key Laboratory for Endocrine and Metabolic Diseases of the National Health Commission of the PR China, Shanghai Key Laboratory for Endocrine Tumor, State Key Laboratory of Medical Genomics, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China
| | - Zhiwen Cao
- Department of Endocrine and Metabolic Diseases, Shanghai Institute of Endocrine and Metabolic Diseases, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China
- Shanghai National Clinical Research Center for Metabolic Diseases, Key Laboratory for Endocrine and Metabolic Diseases of the National Health Commission of the PR China, Shanghai Key Laboratory for Endocrine Tumor, State Key Laboratory of Medical Genomics, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China
| | - Yufei Chen
- Department of Endocrine and Metabolic Diseases, Shanghai Institute of Endocrine and Metabolic Diseases, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China
- Shanghai National Clinical Research Center for Metabolic Diseases, Key Laboratory for Endocrine and Metabolic Diseases of the National Health Commission of the PR China, Shanghai Key Laboratory for Endocrine Tumor, State Key Laboratory of Medical Genomics, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China
| | - Chengcan Yang
- Department of General Surgery, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, 639 Zhizaoju Road, Shanghai, 200011, China
| | - Bing Wang
- Department of General Surgery, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, 639 Zhizaoju Road, Shanghai, 200011, China
| | - Yunqi Li
- Shanghai Institute of Hematology, State Key Laboratory of Medical Genomics, National Research Center for Translational Medicine at Shanghai, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, 197 Ruijin 2nd Road, Shanghai, 200025, China
| | - Bin Li
- Department of Immunology and Microbiology, Shanghai Institute of Immunology, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China
| | - Yufang Bi
- Department of Endocrine and Metabolic Diseases, Shanghai Institute of Endocrine and Metabolic Diseases, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China
- Shanghai National Clinical Research Center for Metabolic Diseases, Key Laboratory for Endocrine and Metabolic Diseases of the National Health Commission of the PR China, Shanghai Key Laboratory for Endocrine Tumor, State Key Laboratory of Medical Genomics, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China
| | - Guang Ning
- Department of Endocrine and Metabolic Diseases, Shanghai Institute of Endocrine and Metabolic Diseases, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China
- Shanghai National Clinical Research Center for Metabolic Diseases, Key Laboratory for Endocrine and Metabolic Diseases of the National Health Commission of the PR China, Shanghai Key Laboratory for Endocrine Tumor, State Key Laboratory of Medical Genomics, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China
| | - Jiqiu Wang
- Department of Endocrine and Metabolic Diseases, Shanghai Institute of Endocrine and Metabolic Diseases, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China
- Shanghai National Clinical Research Center for Metabolic Diseases, Key Laboratory for Endocrine and Metabolic Diseases of the National Health Commission of the PR China, Shanghai Key Laboratory for Endocrine Tumor, State Key Laboratory of Medical Genomics, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China
| | - Weiqing Wang
- Department of Endocrine and Metabolic Diseases, Shanghai Institute of Endocrine and Metabolic Diseases, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China
- Shanghai National Clinical Research Center for Metabolic Diseases, Key Laboratory for Endocrine and Metabolic Diseases of the National Health Commission of the PR China, Shanghai Key Laboratory for Endocrine Tumor, State Key Laboratory of Medical Genomics, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China
| | - Ruixin Liu
- Department of Endocrine and Metabolic Diseases, Shanghai Institute of Endocrine and Metabolic Diseases, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China
- Shanghai National Clinical Research Center for Metabolic Diseases, Key Laboratory for Endocrine and Metabolic Diseases of the National Health Commission of the PR China, Shanghai Key Laboratory for Endocrine Tumor, State Key Laboratory of Medical Genomics, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China
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Sohn W, Lee YS, Kim SS, Kim JH, Jin YJ, Kim GA, Sung PS, Yoo JJ, Chang Y, Lee EJ, Lee HW, Choi M, Yu SJ, Jung YK, Jang BK. KASL clinical practice guidelines for the management of metabolic dysfunction-associated steatotic liver disease 2025. Clin Mol Hepatol 2025; 31:S1-S31. [PMID: 39967303 PMCID: PMC11925433 DOI: 10.3350/cmh.2025.0045] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/13/2025] [Accepted: 02/19/2025] [Indexed: 02/20/2025] Open
Affiliation(s)
- Won Sohn
- Department of Internal Medicine, Kangbuk Samsung Hospital, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Young-Sun Lee
- Department of Internal Medicine, Korea University Guro Hospital, Korea University College of Medicine, Seoul, Korea
| | - Soon Sun Kim
- Department of Internal Medicine, Ajou University School of Medicine, Suwon, Korea
| | - Jung Hee Kim
- Department of Internal Medicine, Dongtan Sacred Heart Hospital, Hallym University School of Medicine, Hwaseong, Korea
| | - Young-Joo Jin
- Department of Internal Medicine, Inha University Hospital, Inha University School of Medicine, Incheon, Korea
| | - Gi-Ae Kim
- Department of Internal Medicine, Kyung Hee University Hospital, Kyung Hee University School of Medicine, Seoul, Korea
| | - Pil Soo Sung
- Department of Internal Medicine, Seoul St. Mary's Hospital, The Catholic University of Korea, Seoul, Korea
| | - Jeong-Ju Yoo
- Department of Internal Medicine, Soonchunhyang University Bucheon Hospital, Bucheon, Korea
| | - Young Chang
- Department of Internal Medicine, Soonchunhyang University Seoul Hospital, Seoul, Korea
| | - Eun Joo Lee
- Department of Pediatrics, Severance Hospital, Yonsei University College of Medicine, Seoul, Korea
| | - Hye Won Lee
- Department of Internal Medicine, Severance Hospital, Yonsei University College of Medicine, Seoul, Korea
| | - Miyoung Choi
- Clinical Evidence Research, National Evidence-Based Healthcare Collaborating Agency, Seoul, Korea
| | - Su Jong Yu
- Department of Internal Medicine and Liver Research Institute, Seoul National University Hospital, Seoul National University College of Medicine, Seoul, Korea
| | - Young Kul Jung
- Department of Internal Medicine, Korea University Ansan Hospital, Korea University College of Medicine, Ansan, Korea
| | - Byoung Kuk Jang
- Department of Internal Medicine, Keimyung University School of Medicine, Daegu, Korea
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Jiang Y, Xu J, Ding J, Liu T, Liu Y, Huang P, Wang Q, Zheng P, Song H, Yang L. Jiangzhi Granule Ameliorates JNK-Mediated Mitochondrial Dysfunction to Reduce Lipotoxic Liver Injury in NASH. Diabetes Metab Syndr Obes 2025; 18:23-36. [PMID: 39802620 PMCID: PMC11721512 DOI: 10.2147/dmso.s492174] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/10/2024] [Accepted: 12/28/2024] [Indexed: 01/16/2025] Open
Abstract
Purpose Mitochondrial dysfunction mediated by c-Jun N-terminal kinase (JNK) plays an important role in lipotoxic liver injury in nonalcoholic steatohepatitis (NASH). This study aims to investigate the pharmacological mechanism of Jiangzhi Granule (JZG), a Chinese herbal formula against NASH, with a focus on its regulation of JNK signaling-mediated mitochondrial function. Methods Hepatocytes were induced by palmitic acid (PA) for 24 h to establish an in vitro lipotoxic model, which was simultaneously treated with either JZG or vehicle control. Male C57BL/6J mice were fed a high-fat diet (HFD) for 22 weeks and then treated with JZG via gavage for additional 8 weeks. Lipotoxic injury in hepatocytes or mice liver tissues, as well as JNK signaling-related molecules, were further investigated. Results JZG improved PA-induced lipid deposition, cell viability, apoptosis, and mitochondrial dysfunction in hepatocytes. In NASH mice, JZG reduced hepatosteatosis, and inflammatory infiltration, and improved mitochondrial morphology and quantity in liver tissues. Additionally, elevated phosphorylation ratio of non-receptor tyrosine kinase c-Src (Src) and reduced phosphorylation ratio of JNK and SH2-containing protein tyrosine phosphatase (SHP-1) were found in both hepatocytes and mice liver tissues treated with JZG versus those with the vehicle. Conclusion Taken together, JZG could improve mitochondrial dysfunction and reduce lipotoxic liver injury in NASH in vivo and in vitro models. The inhibition of the JNK signaling pathway may contribute to the underlying mechanism of JZG in preventing and reversing NASH development.
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Affiliation(s)
- Yuwei Jiang
- Institute of Digestive Diseases, Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, People’s Republic of China
| | - Jiaoya Xu
- Institute of Digestive Diseases, Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, People’s Republic of China
- Department of Gout, Guanghua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, People’s Republic of China
| | - Junyao Ding
- Institute of Digestive Diseases, Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, People’s Republic of China
| | - Tao Liu
- Institute of Digestive Diseases, Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, People’s Republic of China
| | - Yang Liu
- Institute of Digestive Diseases, Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, People’s Republic of China
- Teaching Experiment Center, Shanghai University of Traditional Chinese Medicine, Shanghai, People’s Republic of China
| | - Ping Huang
- Institute of Digestive Diseases, Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, People’s Republic of China
| | - Qianlei Wang
- Institute of Digestive Diseases, Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, People’s Republic of China
| | - Peiyong Zheng
- Institute of Digestive Diseases, Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, People’s Republic of China
| | - Haiyan Song
- Institute of Digestive Diseases, Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, People’s Republic of China
| | - Lili Yang
- Institute of Digestive Diseases, Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, People’s Republic of China
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Gilgenkrantz H, Paradis V, Lotersztajn S. Cell metabolism-based therapy for liver fibrosis, repair, and hepatocellular carcinoma. Hepatology 2025; 81:269-287. [PMID: 37212145 PMCID: PMC11643143 DOI: 10.1097/hep.0000000000000479] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/10/2023] [Accepted: 04/21/2023] [Indexed: 05/23/2023]
Abstract
Progression of chronic liver injury to fibrosis, abnormal liver regeneration, and HCC is driven by a dysregulated dialog between epithelial cells and their microenvironment, in particular immune, fibroblasts, and endothelial cells. There is currently no antifibrogenic therapy, and drug treatment of HCC is limited to tyrosine kinase inhibitors and immunotherapy targeting the tumor microenvironment. Metabolic reprogramming of epithelial and nonparenchymal cells is critical at each stage of disease progression, suggesting that targeting specific metabolic pathways could constitute an interesting therapeutic approach. In this review, we discuss how modulating intrinsic metabolism of key effector liver cells might disrupt the pathogenic sequence from chronic liver injury to fibrosis/cirrhosis, regeneration, and HCC.
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Affiliation(s)
- Hélène Gilgenkrantz
- Paris-Cité University, INSERM, Center for Research on Inflammation, Paris, France
| | - Valérie Paradis
- Paris-Cité University, INSERM, Center for Research on Inflammation, Paris, France
- Pathology Department, Beaujon Hospital APHP, Paris-Cité University, Clichy, France
| | - Sophie Lotersztajn
- Paris-Cité University, INSERM, Center for Research on Inflammation, Paris, France
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Misceo D, Mocciaro G, D'Amore S, Vacca M. Diverting hepatic lipid fluxes with lifestyles revision and pharmacological interventions as a strategy to tackle steatotic liver disease (SLD) and hepatocellular carcinoma (HCC). Nutr Metab (Lond) 2024; 21:112. [PMID: 39716321 DOI: 10.1186/s12986-024-00871-3] [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: 08/22/2024] [Accepted: 11/13/2024] [Indexed: 12/25/2024] Open
Abstract
Steatotic liver disease (SLD) and Hepatocellular Carcinoma (HCC) are characterised by a substantial rewiring of lipid fluxes caused by systemic metabolic unbalances and/or disrupted intracellular metabolic pathways. SLD is a direct consequence of the interaction between genetic predisposition and a chronic positive energy balance affecting whole-body energy homeostasis and the function of metabolically-competent organs. In this review, we discuss how the impairment of the cross-talk between peripheral organs and the liver stalls glucose and lipid metabolism, leading to unbalances in hepatic lipid fluxes that promote hepatic fat accumulation. We also describe how prolonged metabolic stress builds up toxic lipid species in the liver, and how lipotoxicity and metabolic disturbances drive disease progression by promoting a chronic activation of wound healing, leading to fibrosis and HCC. Last, we provide a critical overview of current state of the art (pre-clinical and clinical evidence) regarding mechanisms of action and therapeutic efficacy of candidate SLD treatment options, and their potential to interfere with SLD/HCC pathophysiology by diverting lipids away from the liver therefore improving metabolic health.
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Affiliation(s)
- Davide Misceo
- Department of Interdisciplinary Medicine, Clinica Medica "C. Frugoni", "Aldo Moro" University of Bari, Piazza Giulio Cesare 11, 70124, Bari, Italy
| | - Gabriele Mocciaro
- Roger Williams Institute of Liver Studies, Foundation for Liver Research, London, SE5 9NT, UK
| | - Simona D'Amore
- Department of Precision and Regenerative Medicine and Ionian Area (DiMePRe-J), Clinica Medica "G. Baccelli", "Aldo Moro" University of Bari, 70124, Bari, Italy.
| | - Michele Vacca
- Department of Interdisciplinary Medicine, Clinica Medica "C. Frugoni", "Aldo Moro" University of Bari, Piazza Giulio Cesare 11, 70124, Bari, Italy.
- Roger Williams Institute of Liver Studies, Foundation for Liver Research, London, SE5 9NT, UK.
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Wang Z, Gao P, Gao J, Liang B, Ma Q, Sun Q, Hu Y, Wang Y, Peng Y, Liu H, Wu Y, Yi T, Liu J, Qu LN, Guo H, Shi L, Long J. Daphnetin ameliorates hepatic steatosis by suppressing peroxisome proliferator-activated receptor gamma (PPARG) in ob/ob mice. Biochem Pharmacol 2024; 230:116610. [PMID: 39510197 DOI: 10.1016/j.bcp.2024.116610] [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: 07/02/2024] [Revised: 09/29/2024] [Accepted: 11/04/2024] [Indexed: 11/15/2024]
Abstract
Non-alcoholic fatty liver disease (NAFLD) is the predominant metabolic liver disorder and currently lacks effective and safe pharmaceutical interventions. Daphnetin (DA), a natural coumarin derivative with anti-inflammatory and antioxidant activities, is a promising agent for NAFLD treatment. In this study, we evaluated the effects and mechanisms of DA on hepatic lipid metabolism in ob/ob mice. Our results showed that DA effectively ameliorates glucose metabolism and hepatic lipid accumulation in ob/ob mice. Metabolomics and RNA sequencing (RNA-seq), combined with GEO data analysis, suggest that DA primarily modulates the peroxisome proliferator-activated receptor gamma (PPARG) pathway, as validated in vivo in ob/ob mice. Mechanistically, DA selectively targets PPARG in hepatic cells by inhibiting PPARG promoter activity and downregulating its expression, resulting in decreased transcription of downstream lipid metabolism-related genes, including fatty acid binding protein 4 (Fabp4), cluster of differentiation 36 (Cd36), and fatty acid synthase (Fasn). This effect was abolished in PPARG-deficient HepG2 cells subjected to palmitic acid (PA) insult. Our findings provide evidence that DA acts as a selective suppressor of hepatic PPARG, suggesting an attractive strategy by targeting PPARG for the prevention of hepatic steatosis.
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Affiliation(s)
- Zhen Wang
- Center for Mitochondrial Biology and Medicine, The Key Laboratory of Biomedical Information Engineering of Ministry of Education, School of Life Science, Xi'an Jiaotong University, Xi'an 710049, PR China
| | - Peipei Gao
- Department of Health Education and Management and the Ministry of Education Key Lab of Hazard Assessment and Control in Special Operational Environment, School of Public Health, Fourth Military Medical University, Xi'an 710000, PR China
| | - Jing Gao
- College of Sports and Health Science, Xi'an Physical Education University, Xi'an 710068, PR China
| | - Bing Liang
- First Affiliated Hospital of Jinzhou Medical University, Jinzhou 121001, PR China
| | - Qingqing Ma
- Guizhou Aerospace Hospital, Zunyi 563099, PR China
| | - Qiong Sun
- Yulin Hospital, First Affiliated Hospital of Xi'an Jiao Tong University, Yulin 718000, PR China
| | - Yachong Hu
- Center for Mitochondrial Biology and Medicine, The Key Laboratory of Biomedical Information Engineering of Ministry of Education, School of Life Science, Xi'an Jiaotong University, Xi'an 710049, PR China
| | - Yan Wang
- Department of Stem Cell and Regenerative Medicine, Chinese Academy of Medical Sciences and Peking Union Medical College, Tianjin 300020, PR China
| | - Yunhua Peng
- Center for Mitochondrial Biology and Medicine, The Key Laboratory of Biomedical Information Engineering of Ministry of Education, School of Life Science, Xi'an Jiaotong University, Xi'an 710049, PR China
| | - Huadong Liu
- School of Health and Life Sciences, University of Health and Rehabilitation Sciences, Qingdao 266071, PR China
| | - Yuan Wu
- Department of Endocrinology, First Affiliated Hospital of Medical College, Xi'an Jiaotong University, Xi'an 710000, PR China
| | - Tao Yi
- Faculty of Health Sciences and Sports, Macao Polytechnic University, Macau 999078, PR China
| | - Jiankang Liu
- Center for Mitochondrial Biology and Medicine, The Key Laboratory of Biomedical Information Engineering of Ministry of Education, School of Life Science, Xi'an Jiaotong University, Xi'an 710049, PR China; School of Health and Life Sciences, University of Health and Rehabilitation Sciences, Qingdao 266071, PR China
| | - Li-Na Qu
- Department of Cellular and Molecular Biology, State Key Laboratory of Space Medicine Fundamentals and Application, China Astronaut Research and Training Center, Beijing 100094, PR China
| | - Hui Guo
- Department of Endocrinology, First Affiliated Hospital of Medical College, Xi'an Jiaotong University, Xi'an 710000, PR China.
| | - Le Shi
- Center for Mitochondrial Biology and Medicine, The Key Laboratory of Biomedical Information Engineering of Ministry of Education, School of Life Science, Xi'an Jiaotong University, Xi'an 710049, PR China.
| | - Jiangang Long
- Center for Mitochondrial Biology and Medicine, The Key Laboratory of Biomedical Information Engineering of Ministry of Education, School of Life Science, Xi'an Jiaotong University, Xi'an 710049, PR China.
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9
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Vu HT, Nguyen VD, Ikenaga H, Matsubara T. Application of PPAR Ligands and Nanoparticle Technology in Metabolic Steatohepatitis Treatment. Biomedicines 2024; 12:1876. [PMID: 39200340 PMCID: PMC11351628 DOI: 10.3390/biomedicines12081876] [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: 07/29/2024] [Revised: 08/10/2024] [Accepted: 08/13/2024] [Indexed: 09/02/2024] Open
Abstract
Metabolic dysfunction-associated steatotic liver disease/steatohepatitis (MASLD/MASH) is a major disease worldwide whose effective treatment is challenging. Peroxisome proliferator-activated receptors (PPARs) belong to the nuclear receptor superfamily and function as ligand-activated transcription factors. To date, three distinct subtypes of PPARs have been characterized: PPARα, PPARβ/δ, and PPARγ. PPARα and PPARγ are crucial regulators of lipid metabolism that modulate the transcription of genes involved in fatty acid (FA), bile acid, and cholesterol metabolism. Many PPAR agonists, including natural (FAs, eicosanoids, and phospholipids) and synthetic (fibrate, thiazolidinedione, glitazar, and elafibranor) agonists, have been developed. Furthermore, recent advancements in nanoparticles (NPs) have led to the development of new strategies for MASLD/MASH therapy. This review discusses the applications of specific cell-targeted NPs and highlights the potential of PPARα- and PPARγ-targeted NP drug delivery systems for MASLD/MASH treatment.
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Affiliation(s)
- Hung Thai Vu
- Department of Anatomy and Regenerative Biology, Graduate School of Medicine, Osaka Metropolitan University, Osaka 545-8585, Osaka, Japan; (H.T.V.); (V.D.N.)
| | - Vien Duc Nguyen
- Department of Anatomy and Regenerative Biology, Graduate School of Medicine, Osaka Metropolitan University, Osaka 545-8585, Osaka, Japan; (H.T.V.); (V.D.N.)
| | - Hiroko Ikenaga
- Department of Hepatology, Graduate School of Medicine, Osaka Metropolitan University, Osaka 545-8585, Osaka, Japan
| | - Tsutomu Matsubara
- Department of Anatomy and Regenerative Biology, Graduate School of Medicine, Osaka Metropolitan University, Osaka 545-8585, Osaka, Japan; (H.T.V.); (V.D.N.)
- Research Institute for Light-induced Acceleration System (RILACS), Osaka Metropolitan University, Sakai 599-8570, Osaka, Japan
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10
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Petta S, Targher G, Romeo S, Pajvani UB, Zheng MH, Aghemo A, Valenti LVC. The first MASH drug therapy on the horizon: Current perspectives of resmetirom. Liver Int 2024; 44:1526-1536. [PMID: 38578141 DOI: 10.1111/liv.15930] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/26/2024] [Accepted: 03/27/2024] [Indexed: 04/06/2024]
Abstract
The rising prevalence of metabolic dysfunction-associated steatotic liver disease (MASLD) poses a significant global health challenge, affecting over 30% of adults worldwide. MASLD is linked to increased mortality rates and substantial healthcare costs, primarily driven by its progression to metabolic dysfunction-associated steatohepatitis (MASH), which can lead to severe liver complications including cirrhosis and hepatocellular carcinoma. Despite its growing burden, effective pharmacotherapy for MASLD/MASH has been lacking until the recent conditional approval of resmetirom by the FDA. Resmetirom, a liver-targeted thyroid hormone receptor-β selective drug, has shown promise in clinical trials for treating non-cirrhotic MASH with moderate to advanced fibrosis. It has demonstrated efficacy in reducing hepatic fat content, improving liver histology (both MASH resolution and fibrosis improvement), and ameliorating biomarkers of liver damage without significant effects on body weight or glucose metabolism. Notably, resmetirom also exhibits favourable effects on circulating lipids, potentially reducing cardiovascular risk in MASLD/MASH patients. The safety profile of resmetirom appears acceptable, with gastrointestinal adverse events being the most common, though generally mild or moderate. However, long-term surveillance is warranted to monitor for potential risks related to thyroid, gonadal, or bone diseases. Clinical implementation of resmetirom faces challenges in patient selection and monitoring treatment response, and will heavily rely on non-invasive tests for liver fibrosis assessment. Nonetheless, resmetirom represents a landmark breakthrough in MASLD/MASH treatment, paving the way for future therapeutic strategies aiming to mitigate the multifaceted risks associated with this complex metabolic liver disease.
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Affiliation(s)
- Salvatore Petta
- Gastroenterology and Hepatology, PROMISE, Università di Palermo, Palermo, Italy
| | - Giovanni Targher
- Department of Medicine, University of Verona, Verona, Italy
- Metabolic Diseases Research Unit, IRCCS Sacro Cuore - Don Calabria Hospital, Negrar di Valpolicella, Italy
| | - Stefano Romeo
- Wallenberg Laboratory, Department of Molecular and Clinical Medicine, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
- Clinical Nutrition Unit, Department of Medical and Surgical Science, University Magna Graecia, Catanzaro, Italy
- Department of Cardiology, Sahlgrenska University Hospital, Gothenburg, Sweden
| | - Utpal B Pajvani
- Department of Medicine and Naomi Berrie Diabetes Center, Columbia University Irving Medical Center, New York, New York, USA
| | - Ming-Hua Zheng
- Department of Hepatology, MAFLD Research Center, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
- Key Laboratory of Diagnosis and Treatment for The Development of Chronic Liver Disease in Zhejiang Province, Wenzhou, China
| | - Alessio Aghemo
- Division of Internal Medicine and Hepatology, Department of Gastroenterology, IRCCS Humanitas Research Hospital, Rozzano, Italy
- Department of Biomedical Sciences, Humanitas University, Pieve Emanuele, Italy
| | - Luca V C Valenti
- Department of Pathophysiology and Transplantation, Università degli Studi di Milano, Milan, Italy
- Precision Medicine, Biological Resource Center Unit, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy
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11
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Cooreman MP, Vonghia L, Francque SM. MASLD/MASH and type 2 diabetes: Two sides of the same coin? From single PPAR to pan-PPAR agonists. Diabetes Res Clin Pract 2024; 212:111688. [PMID: 38697298 DOI: 10.1016/j.diabres.2024.111688] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 04/24/2024] [Indexed: 05/04/2024]
Abstract
Type 2 diabetes (T2D) and metabolic dysfunction-associated steatotic liver disease (MASLD), mainly related to nutrition and lack of physical activity, are both very common conditions, share several disease pathways and clinical manifestations, and increasingly co-occur with disease progression. Insulin resistance is an upstream node in the biology of both conditions and triggers liver parenchymal injury, inflammation and fibrosis. Peroxisome proliferator-activated receptor (PPAR) nuclear transcription factors are master regulators of energy homeostasis - insulin signaling in liver, adipose and skeletal muscle tissue - and affect immune and fibrogenesis pathways. Among distinct yet overlapping effects, PPARα regulates lipid metabolism and energy expenditure, PPARβ/δ has anti-inflammatory effects and increases glucose uptake by skeletal muscle, while PPARγ improves insulin sensitivity and exerts direct antifibrotic effects on hepatic stellate cells. Together PPARs thus represent pharmacological targets across the entire biology of MASH. Single PPAR agonists are approved for hypertriglyceridemia (PPARα) and T2D (PPARγ), but these, as well as dual PPAR agonists, have shown mixed results as anti-MASH treatments in clinical trials. Agonists of all three PPAR isoforms have the potential to improve the full disease spectrum from insulin resistance to fibrosis, and correspondingly to improve cardiometabolic and hepatic health, as has been shown (phase II data) with the pan-PPAR agonist lanifibranor.
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Affiliation(s)
- Michael P Cooreman
- Research and Development, Inventiva, Daix, France; Research and Development, Inventiva, New York, NY, USA.
| | - Luisa Vonghia
- Department of Gastroenterology and Hepatology, Antwerp University Hospital, Edegem, Belgium; InflaMed Centre of Excellence, Laboratory for Experimental Medicine and Paediatrics, Translational Sciences in Inflammation and Immunology, Faculty of Medicine and Health Sciences, University of Antwerp, Wilrijk, Belgium
| | - Sven M Francque
- Department of Gastroenterology and Hepatology, Antwerp University Hospital, Edegem, Belgium; InflaMed Centre of Excellence, Laboratory for Experimental Medicine and Paediatrics, Translational Sciences in Inflammation and Immunology, Faculty of Medicine and Health Sciences, University of Antwerp, Wilrijk, Belgium.
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12
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Zhu S, Wu Z, Wang W, Wei L, Zhou H. A revisit of drugs and potential therapeutic targets against non-alcoholic fatty liver disease: learning from clinical trials. J Endocrinol Invest 2024; 47:761-776. [PMID: 37839037 DOI: 10.1007/s40618-023-02216-y] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/02/2023] [Accepted: 10/01/2023] [Indexed: 10/17/2023]
Abstract
PURPOSE Non-alcoholic fatty liver disease (NAFLD) is the most common liver disease, with a worldwide prevalence of 25%. Although numerous clinical trials have been conducted over the last few decades, an effective treatment has not been approved yet. Extensive research has accumulated a large amount of data and experience; however, the vast number of clinical trials and new therapeutic targets for NAFLD make it impossible to keep abreast of the relevant information. Therefore, a systematic analysis of the existing trials is necessary. METHODS Here, we reviewed clinical trials on NAFLD registered in the mandated federal database, ClinicalTrials.gov, to generate a detailed overview of the trials related to drugs and therapeutic targets for NAFLD treatment. Following screening for pertinence to therapy, a total of 440 entries were identified that included active trials as well as those that have already been completed, suspended, terminated, or withdrawn. RESULTS We summarize and systematically analyze the state, drug development pipeline, and discovery of treatment targets for NAFLD. We consider possible factors that may affect clinical outcomes. Furthermore, we discussed these results to explore the mechanisms responsible for clinical outcomes. CONCLUSION We summarised the landscape of current clinical trials and suggested the directions for future NAFLD therapy to assist internal medicine specialists in treating the whole clinical spectrum of this highly prevalent liver disease.
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Affiliation(s)
- S Zhu
- Wuxi School of Medicine, Jiangnan University, Wuxi, China
| | - Z Wu
- Wuxi School of Medicine, Jiangnan University, Wuxi, China
| | - W Wang
- Wuxi School of Medicine, Jiangnan University, Wuxi, China
| | - L Wei
- School of Life Science, Anhui Medical University, Hefei, 230032, China.
| | - H Zhou
- School of Life Science, Anhui Medical University, Hefei, 230032, China.
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13
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Kumar J, Mohsin S, Hasan M, Bilal AR, Ali KM, Umer A, Hadi DZM, Nandlal S, Kumar S. Cardiovascular outcomes post bariatric surgery in patients with metabolic dysfunction-associated steatotic liver disease - A systematic review and meta-analysis. Clin Res Hepatol Gastroenterol 2024; 48:102261. [PMID: 38070828 DOI: 10.1016/j.clinre.2023.102261] [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: 09/22/2023] [Revised: 12/03/2023] [Accepted: 12/04/2023] [Indexed: 01/13/2024]
Abstract
BACKGROUND Metabolic dysfunction-associated steatotic liver disease (MASLD), previously known as non-alcoholic fatty liver disease (NAFLD), is linked with an increased risk of adverse cardiovascular events. Studies have suggested an association between the reduction of incident cardiovascular events in patients with MASLD after bariatric surgery. This systematic review and meta-analysis were performed to assess the influence of bariatric surgery on cardiovascular outcomes in patients with diagnosed MASLD by identifying all available cohort studies and pooling their data. METHODS PubMed and Google Scholar databases were searched till July 2023 for published studies that assessed the effect of bariatric surgery on cardiovascular outcomes in MASLD patients. Using a random effects model, hazard ratios (HRs) with 95 % confidence intervals (CIs) were pooled. RESULTS The systematic review identified three cohort studies. The analysis of 240,516 MASLD patients found a significantly reduced incidence of cardiovascular events. (HR 0.51; 95 % CI 0.48 to 0.54, P value <0.00001). CONCLUSION Bariatric surgery in MASLD patients significantly reduced the incidence of cardiovascular events, suggesting that bariatric surgery is an effective therapeutic tool among MASLD patients compared to non-surgical interventions.
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Affiliation(s)
- Jai Kumar
- School of Medicine, Wayne State University, Detroit, MI, United States
| | - Sana Mohsin
- Ziauddin Medical College, 4/B, Saharah-e-Ghalib, Block 6, Clifton, Karachi, Sindh 75600, Pakistan
| | - Misha Hasan
- Ziauddin Medical College, 4/B, Saharah-e-Ghalib, Block 6, Clifton, Karachi, Sindh 75600, Pakistan.
| | - Abdur Raheem Bilal
- Ziauddin Medical College, 4/B, Saharah-e-Ghalib, Block 6, Clifton, Karachi, Sindh 75600, Pakistan
| | | | - Ahmed Umer
- Ziauddin Medical College, 4/B, Saharah-e-Ghalib, Block 6, Clifton, Karachi, Sindh 75600, Pakistan
| | | | - Sanjna Nandlal
- Ziauddin Medical College, 4/B, Saharah-e-Ghalib, Block 6, Clifton, Karachi, Sindh 75600, Pakistan
| | - Sarwan Kumar
- School of Medicine, Wayne State University, Detroit, MI, United States
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14
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Staels B, Butruille L, Francque S. Treating NASH by targeting peroxisome proliferator-activated receptors. J Hepatol 2023; 79:1302-1316. [PMID: 37459921 DOI: 10.1016/j.jhep.2023.07.004] [Citation(s) in RCA: 38] [Impact Index Per Article: 19.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/31/2023] [Revised: 06/18/2023] [Accepted: 07/02/2023] [Indexed: 09/15/2023]
Abstract
The pathophysiology of non-alcoholic steatohepatitis (NASH) encompasses a complex set of intra- and extrahepatic driving mechanisms, involving numerous metabolic, inflammatory, vascular and fibrogenic pathways. The peroxisome proliferator-activated receptors (PPARs) α, β/δ and γ belong to the nuclear receptor family of ligand-activated transcription factors. Activated PPARs modulate target tissue transcriptomic profiles, enabling the body's adaptation to changing nutritional, metabolic and inflammatory environments. PPARs hence regulate several pathways involved in NASH pathogenesis. Whereas single PPAR agonists exert robust anti-NASH activity in several preclinical models, their clinical effects on histological endpoints of NASH resolution and fibrosis regression appear more modest. Simultaneous activation of several PPAR isotypes across different organs and within-organ cell types, resulting in pleiotropic actions, enhances the therapeutic potential of PPAR agonists as pharmacological agents for NASH and NASH-related hepatic and extrahepatic morbidity, with some compounds having already shown clinical efficacy on histological endpoints.
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Affiliation(s)
- Bart Staels
- University of Lille, Inserm, CHU Lille, Institut Pasteur de Lille, U1011-EGID, Lille, France.
| | - Laura Butruille
- University of Lille, Inserm, CHU Lille, Institut Pasteur de Lille, U1011-EGID, Lille, France
| | - Sven Francque
- Department of Gastroenterology Hepatology, Antwerp University Hospital, Drie Eikenstraat 655, B-2650, Edegem, Belgium; InflaMed Centre of Excellence, Laboratory for Experimental Medicine and Paediatrics, Translational Sciences in Inflammation and Immunology, Faculty of Medicine and Health Sciences, University of Antwerp, Universiteitsplein 1, B-2610, Wilrijk, Belgium.
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15
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Grander C, Meyer M, Steinacher D, Claudel T, Hausmann B, Pjevac P, Grabherr F, Oberhuber G, Grander M, Brigo N, Jukic A, Schwärzler J, Weiss G, Adolph TE, Trauner M, Tilg H. 24-Norursodeoxycholic acid ameliorates experimental alcohol-related liver disease and activates hepatic PPARγ. JHEP Rep 2023; 5:100872. [PMID: 37818230 PMCID: PMC10561126 DOI: 10.1016/j.jhepr.2023.100872] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/13/2022] [Revised: 05/23/2023] [Accepted: 07/12/2023] [Indexed: 10/12/2023] Open
Abstract
Background & Aims Alcohol-related liver disease (ALD) is a global healthcare challenge with limited treatment options. 24-Norursodeoxycholic acid (NorUDCA) is a synthetic bile acid with anti-inflammatory properties in experimental and human cholestatic liver diseases. In the present study, we explored the efficacy of norUDCA in experimental ALD. Methods NorUDCA was tested in a preventive and therapeutic setting in an experimental ALD model (Lieber-DeCarli diet enriched with ethanol). Liver disease was phenotypically evaluated using histology and biochemical methods, and anti-inflammatory properties and peroxisome proliferator-activated receptor gamma activation by norUDCA were evaluated in cellular model systems. Results NorUDCA administration ameliorated ethanol-induced liver injury, reduced hepatocyte death, and reduced the expression of hepatic pro-inflammatory cytokines including tumour necrosis factor (Tnf), Il-1β, Il-6, and Il-10. NorUDCA shifted hepatic macrophages towards an anti-inflammatory M2 phenotype. Further, norUDCA administration altered the composition of the intestinal microbiota, specifically increasing the abundance of Roseburia, Enterobacteriaceae, and Clostridum spp. In a therapeutic model, norUDCA also ameliorated ethanol-induced liver injury. Moreover, norUDCA suppressed lipopolysaccharide-induced IL-6 expression in human peripheral blood mononuclear cells and evoked peroxisome proliferator-activated receptor gamma activation. Conclusions NorUDCA ameliorated experimental ALD, protected against hepatic inflammation, and affected gut microbial commensalism. NorUDCA could serve as a novel therapeutic agent in the future management of patients with ALD. Impact and implications Alcohol-related liver disease is a global healthcare concern with limited treatment options. 24-Norursodeoxycholic acid (NorUDCA) is a modified bile acid, which was proven to be effective in human cholestatic liver diseases. In the present study, we found a protective effect of norUDCA in experimental alcoholic liver disease. For patients with ALD, norUDCA could be a potential new treatment option.
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Affiliation(s)
- Christoph Grander
- Department of Internal Medicine I, Gastroenterology, Hepatology, Endocrinology and Metabolism, Medical University Innsbruck, Innsbruck, Austria
| | - Moritz Meyer
- Department of Internal Medicine I, Gastroenterology, Hepatology, Endocrinology and Metabolism, Medical University Innsbruck, Innsbruck, Austria
| | - Daniel Steinacher
- Hans Popper Laboratory of Molecular Hepatology, Department of Internal Medicine III, Division of Gastroenterology and Hepatology, Medical University of Vienna, Vienna, Austria
| | - Thierry Claudel
- Hans Popper Laboratory of Molecular Hepatology, Department of Internal Medicine III, Division of Gastroenterology and Hepatology, Medical University of Vienna, Vienna, Austria
| | - Bela Hausmann
- Joint Microbiome Facility of the Medical University of Vienna, The University of Vienna, Vienna, Austria
- Department of Laboratory Medicine, Medical University of Vienna, Vienna, Austria
| | - Petra Pjevac
- Joint Microbiome Facility of the Medical University of Vienna, The University of Vienna, Vienna, Austria
- Division of Microbial Ecology, Department of Microbiology and Ecosystem Science, Centre for Microbiology and Environmental Systems Science, University of Vienna, Vienna, Austria
| | - Felix Grabherr
- Department of Internal Medicine I, Gastroenterology, Hepatology, Endocrinology and Metabolism, Medical University Innsbruck, Innsbruck, Austria
| | - Georg Oberhuber
- INNPATH, Tirol-Kliniken University Hospital Innsbruck, Innsbruck, Austria
| | - Manuel Grander
- Department of Internal Medicine II, Infectious Diseases, Immunology, Rheumatology, Pneumology, Medical University Innsbruck, Innsbruck, Austria
| | - Natascha Brigo
- Department of Internal Medicine II, Infectious Diseases, Immunology, Rheumatology, Pneumology, Medical University Innsbruck, Innsbruck, Austria
| | - Almina Jukic
- Department of Internal Medicine I, Gastroenterology, Hepatology, Endocrinology and Metabolism, Medical University Innsbruck, Innsbruck, Austria
| | - Julian Schwärzler
- Department of Internal Medicine I, Gastroenterology, Hepatology, Endocrinology and Metabolism, Medical University Innsbruck, Innsbruck, Austria
| | - Günter Weiss
- Department of Internal Medicine II, Infectious Diseases, Immunology, Rheumatology, Pneumology, Medical University Innsbruck, Innsbruck, Austria
| | - Timon E. Adolph
- Department of Internal Medicine I, Gastroenterology, Hepatology, Endocrinology and Metabolism, Medical University Innsbruck, Innsbruck, Austria
| | - Michael Trauner
- Hans Popper Laboratory of Molecular Hepatology, Department of Internal Medicine III, Division of Gastroenterology and Hepatology, Medical University of Vienna, Vienna, Austria
| | - Herbert Tilg
- Department of Internal Medicine I, Gastroenterology, Hepatology, Endocrinology and Metabolism, Medical University Innsbruck, Innsbruck, Austria
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16
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Zhang Y, Xu J, Zhou D, Ye T, Zhou P, Liu Z, Liu X, Wang Z, Hua T, Zhang Z, Sun Q. Swimming exercise ameliorates insulin resistance and nonalcoholic fatty liver by negatively regulating PPARγ transcriptional network in mice fed high fat diet. Mol Med 2023; 29:150. [PMID: 37907845 PMCID: PMC10617119 DOI: 10.1186/s10020-023-00740-4] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/14/2023] [Accepted: 10/16/2023] [Indexed: 11/02/2023] Open
Abstract
BACKGROUND Recent findings elucidated hepatic PPARγ functions as a steatogenic-inducer gene that activates de novo lipogenesis, and is involved in regulation of glucose homeostasis, lipid accumulation, and inflammation response. This study delved into a comprehensive analysis of how PPARγ signaling affects the exercise-induced improvement of insulin resistance (IR) and non-alcoholic fatty liver disease (NAFLD), along with its underlying mechanism. METHODS Chronic and acute swimming exercise intervention were conducted in each group mice. IR status was assessed by GTT and ITT assays. Serum inflammatory cytokines were detected by Elisa assays. PPARγ and its target genes expression were detected by qPCR assay. Relative protein levels were quantified via Western blotting. ChIP-qPCR assays were used to detect the enrichment of PPARγ on its target genes promoter. RESULTS Through an exploration of a high-fat diet (HFD)-induced IR and NAFLD model, both chronic and acute swimming exercise training led to significant reductions in body weight and visceral fat mass, as well as hepatic lipid accumulation. The exercise interventions also demonstrated a significant amelioration in IR and the inflammatory response. Meanwhile, swimming exercise significantly inhibited PPARγ and its target genes expression induced by HFD, containing CD36, SCD1 and PLIN2. Furthermore, swimming exercise presented significant modulation on regulatory factors of PPARγ expression and transcriptional activity. CONCLUSION The findings suggest that swimming exercise can improve lipid metabolism in IR and NAFLD, possibly through PPARγ signaling in the liver of mice.
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Affiliation(s)
- Yong Zhang
- Physiology laboratory of College of Life Sciences, Anhui Normal University, Wuhu, China
- the State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Biology, School of Life Sciences, Xiamen University, Xiamen, China
| | - Jie Xu
- Department of Hepatology, Affiliated Hospital of Panzhihua University, Panzhihua, China
| | - Di Zhou
- Physiology laboratory of College of Life Sciences, Anhui Normal University, Wuhu, China
| | - Tingting Ye
- Physiology laboratory of College of Life Sciences, Anhui Normal University, Wuhu, China
| | - Puqing Zhou
- Physiology laboratory of College of Life Sciences, Anhui Normal University, Wuhu, China
| | - Zuofeng Liu
- Department of Hepatology, Affiliated Hospital of Panzhihua University, Panzhihua, China
| | - Xinyuan Liu
- the State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Biology, School of Life Sciences, Xiamen University, Xiamen, China
| | - Zinan Wang
- the State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Biology, School of Life Sciences, Xiamen University, Xiamen, China
| | - Tianmiao Hua
- Physiology laboratory of College of Life Sciences, Anhui Normal University, Wuhu, China
| | - Zhenghao Zhang
- Department of Hematology, People's Hospital of Xinjiang Uygur Autonomous Region, Urumqi, China.
| | - Qingyan Sun
- Physiology laboratory of College of Life Sciences, Anhui Normal University, Wuhu, China.
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17
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Kamata S, Honda A, Ishii I. Current Clinical Trial Status and Future Prospects of PPAR-Targeted Drugs for Treating Nonalcoholic Fatty Liver Disease. Biomolecules 2023; 13:1264. [PMID: 37627329 PMCID: PMC10452531 DOI: 10.3390/biom13081264] [Citation(s) in RCA: 22] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/01/2023] [Revised: 08/16/2023] [Accepted: 08/17/2023] [Indexed: 08/27/2023] Open
Abstract
The number of patients with nonalcoholic fatty liver disease (NAFLD)/nonalcoholic steatohepatitis (NASH) is increasing globally and is raising serious concerns regarding the increasing medical and economic burden incurred for their treatment. The progression of NASH to more severe conditions such as cirrhosis and hepatocellular carcinoma requires liver transplantation to avoid death. Therefore, therapeutic intervention is required in the NASH stage, although no therapeutic drugs are currently available for this. Several anti-NASH candidate drugs have been developed that enable treatment via the modulation of distinct signaling cascades and include a series of drugs targeting peroxisome proliferator-activated receptor (PPAR) subtypes (PPARα/δ/γ) that are considered to be attractive because they can regulate both systemic lipid metabolism and inflammation. Multiple PPAR dual/pan agonists have been developed but only a few of them have been evaluated in clinical trials for NAFLD/NASH. Herein, we review the current clinical trial status and future prospects of PPAR-targeted drugs for treating NAFLD/NASH. In addition, we summarize our recent findings on the binding modes and the potencies/efficacies of several candidate PPAR dual/pan agonists to estimate their therapeutic potentials against NASH. Considering that the development of numerous PPAR dual/pan agonists has been abandoned because of their serious side effects, we also propose a repositioning of the already approved, safety-proven PPAR-targeted drugs against NAFLD/NASH.
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Affiliation(s)
| | | | - Isao Ishii
- Department of Health Chemistry, Showa Pharmaceutical University, Machida, Tokyo 194-8543, Japan; (S.K.); (A.H.)
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18
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Zheng Y, Wang S, Wu J, Wang Y. Mitochondrial metabolic dysfunction and non-alcoholic fatty liver disease: new insights from pathogenic mechanisms to clinically targeted therapy. J Transl Med 2023; 21:510. [PMID: 37507803 PMCID: PMC10375703 DOI: 10.1186/s12967-023-04367-1] [Citation(s) in RCA: 38] [Impact Index Per Article: 19.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/08/2023] [Accepted: 07/17/2023] [Indexed: 07/30/2023] Open
Abstract
Metabolic dysfunction-associated fatty liver disease (MAFLD) is among the most widespread metabolic disease globally, and its associated complications including insulin resistance and diabetes have become threatening conditions for human health. Previous studies on non-alcoholic fatty liver disease (NAFLD) were focused on the liver's lipid metabolism. However, growing evidence suggests that mitochondrial metabolism is involved in the pathogenesis of NAFLD to varying degrees in several ways, for instance in cellular division, oxidative stress, autophagy, and mitochondrial quality control. Ultimately, liver function gradually declines as a result of mitochondrial dysfunction. The liver is unable to transfer the excess lipid droplets outside the liver. Therefore, how to regulate hepatic mitochondrial function to treat NAFLD has become the focus of current research. This review provides details about the intrinsic link of NAFLD with mitochondrial metabolism and the mechanisms by which mitochondrial dysfunctions contribute to NAFLD progression. Given the crucial role of mitochondrial metabolism in NAFLD progression, the application potential of multiple mitochondrial function improvement modalities (including physical exercise, diabetic medications, small molecule agonists targeting Sirt3, and mitochondria-specific antioxidants) in the treatment of NAFLD was evaluated hoping to provide new insights into NAFLD treatment.
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Affiliation(s)
- Youwei Zheng
- Department of General Surgery, The Fourth Affiliated Hospital of China Medical University, Shenyang, Liaoning Province, China
| | - Shiting Wang
- Department of Cardiovascular Medicine, The Fourth Affiliated Hospital of China Medical University, Shenyang, China
| | - Jialiang Wu
- Department of General Surgery, The Fourth Affiliated Hospital of China Medical University, Shenyang, Liaoning Province, China
| | - Yong Wang
- Department of General Surgery, The Fourth Affiliated Hospital of China Medical University, Shenyang, Liaoning Province, China.
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19
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Amatya R, Lee D, Min KA, Shin MC. Pharmaceutical Strategies to Improve Druggability of Potential Drug Candidates in Nonalcoholic Fatty Liver Disease Therapy. Pharmaceutics 2023; 15:1963. [PMID: 37514148 PMCID: PMC10386216 DOI: 10.3390/pharmaceutics15071963] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/13/2023] [Revised: 07/10/2023] [Accepted: 07/12/2023] [Indexed: 07/30/2023] Open
Abstract
Nonalcoholic fatty liver disease (NAFLD) has become globally prevalent and is the leading cause of chronic liver disease. Although NAFLD is reversible without medical intervention in the early stage, the condition could be sequentially worsened to nonalcoholic steatohepatitis (NASH) and, eventually, cirrhosis and hepatic cancer. The progression of NAFLD is related to various factors such as genetics, pre-disposed metabolic disorders, and immunologic factors. Thankfully, to date, there have been accumulating research efforts and, as a result, different classes of potent drug candidates have been discovered. In addition, there have also been various attempts to explore pharmaceutical strategies to improve the druggability of drug candidates. In this review, we provided a brief overview of the drug candidates that have undergone clinical trials. In the latter part, strategies for developing better drugs are discussed.
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Affiliation(s)
- Reeju Amatya
- College of Pharmacy and Research Institute of Pharmaceutical Sciences, Gyeongsang National University, 501 Jinju Daero, Jinju 52828, Republic of Korea
| | - Donghee Lee
- College of Pharmacy and Research Institute of Pharmaceutical Sciences, Gyeongsang National University, 501 Jinju Daero, Jinju 52828, Republic of Korea
| | - Kyoung Ah Min
- College of Pharmacy and Inje Institute of Pharmaceutical Sciences and Research, Inje University, 197 Injero, Gimhae 50834, Republic of Korea
| | - Meong Cheol Shin
- College of Pharmacy and Research Institute of Pharmaceutical Sciences, Gyeongsang National University, 501 Jinju Daero, Jinju 52828, Republic of Korea
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20
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Yang S, Duan Z, Zhang S, Fan C, Zhu C, Fu R, Ma X, Fan D. Ginsenoside Rh4 Improves Hepatic Lipid Metabolism and Inflammation in a Model of NAFLD by Targeting the Gut Liver Axis and Modulating the FXR Signaling Pathway. Foods 2023; 12:2492. [PMID: 37444230 DOI: 10.3390/foods12132492] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/13/2023] [Revised: 06/04/2023] [Accepted: 06/09/2023] [Indexed: 07/15/2023] Open
Abstract
Non-alcoholic fatty liver disease (NAFLD) is a series of disorders of liver metabolism caused by the accumulation of lipids in the liver, which is considered the main cause of hepatocellular carcinoma. Our previous study demonstrated the promising efficacy of ginsenoside Rh4 in improving the intestinal tract and its related metabolites. Meanwhile, many studies in the literature have investigated the gut microbiota and its metabolites, such as bile acids (BAs) and short-chain fatty acids (SCFAs), which play a key role in the pathogenesis of NAFLD. Therefore, this study focused on whether Rh4 could achieve therapeutic effects on NAFLD through the gut-liver axis. The results showed that Rh4 exhibited sound therapeutic effects on the NAFLD model induced by the Western diet and CCl4 in mice. In the liver, the degrees of hepatic steatosis, lobular inflammation levels, and bile acid in the liver tissue were improved after Rh4 treatment. At the same time, Rh4 treatment significantly increased the levels of intestinal SCFAs and BAs, and these changes were accompanied by the complementary diversity and composition of intestinal flora. In addition, correlation analysis showed that Rh4 affected the expression of proteins involved in the farnesoid X receptor (FXR) signaling pathway in the liver and intestine, which modulates hepatic lipid metabolism, inflammation, and proteins related to bile acid regulation. In conclusion, our study provides a valuable insight into how Rh4 targets the gut-liver axis for the development of NAFLD, which indicates that Rh4 may be a promising candidate for the clinical therapy of NAFLD.
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Affiliation(s)
- Siming Yang
- Shaanxi Key Laboratory of Degradable Biomedical Materials, School of Chemical Engineering, Northwest University, Xi'an 710127, China
- Shaanxi R&D Center of Biomaterials and Fermentation Engineering, School of Chemical Engineering, Northwest University, Xi'an 710069, China
- Biotechnology & Biomed, Research Institute, School of Chemical Engineering, Northwest University, 229 North Taibai Road, Xi'an 710069, China
| | - Zhiguang Duan
- Shaanxi Key Laboratory of Degradable Biomedical Materials, School of Chemical Engineering, Northwest University, Xi'an 710127, China
- Shaanxi R&D Center of Biomaterials and Fermentation Engineering, School of Chemical Engineering, Northwest University, Xi'an 710069, China
- Biotechnology & Biomed, Research Institute, School of Chemical Engineering, Northwest University, 229 North Taibai Road, Xi'an 710069, China
| | - Sen Zhang
- Shaanxi Key Laboratory of Degradable Biomedical Materials, School of Chemical Engineering, Northwest University, Xi'an 710127, China
- Shaanxi R&D Center of Biomaterials and Fermentation Engineering, School of Chemical Engineering, Northwest University, Xi'an 710069, China
- Biotechnology & Biomed, Research Institute, School of Chemical Engineering, Northwest University, 229 North Taibai Road, Xi'an 710069, China
| | - Cuiying Fan
- Xi'an Giant Biogene Technology Co., Ltd., No. 20, Zone C, Venture R&D Park, No. 69, Jinye Road, High-tech Zone, Xi'an 710077, China
| | - Chenhui Zhu
- Shaanxi Key Laboratory of Degradable Biomedical Materials, School of Chemical Engineering, Northwest University, Xi'an 710127, China
- Shaanxi R&D Center of Biomaterials and Fermentation Engineering, School of Chemical Engineering, Northwest University, Xi'an 710069, China
- Biotechnology & Biomed, Research Institute, School of Chemical Engineering, Northwest University, 229 North Taibai Road, Xi'an 710069, China
| | - Rongzhan Fu
- Shaanxi Key Laboratory of Degradable Biomedical Materials, School of Chemical Engineering, Northwest University, Xi'an 710127, China
- Shaanxi R&D Center of Biomaterials and Fermentation Engineering, School of Chemical Engineering, Northwest University, Xi'an 710069, China
- Biotechnology & Biomed, Research Institute, School of Chemical Engineering, Northwest University, 229 North Taibai Road, Xi'an 710069, China
| | - Xiaoxuan Ma
- Shaanxi Key Laboratory of Degradable Biomedical Materials, School of Chemical Engineering, Northwest University, Xi'an 710127, China
- Shaanxi R&D Center of Biomaterials and Fermentation Engineering, School of Chemical Engineering, Northwest University, Xi'an 710069, China
- Biotechnology & Biomed, Research Institute, School of Chemical Engineering, Northwest University, 229 North Taibai Road, Xi'an 710069, China
| | - Daidi Fan
- Shaanxi Key Laboratory of Degradable Biomedical Materials, School of Chemical Engineering, Northwest University, Xi'an 710127, China
- Shaanxi R&D Center of Biomaterials and Fermentation Engineering, School of Chemical Engineering, Northwest University, Xi'an 710069, China
- Biotechnology & Biomed, Research Institute, School of Chemical Engineering, Northwest University, 229 North Taibai Road, Xi'an 710069, China
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21
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Zaiou M. Peroxisome Proliferator-Activated Receptor-γ as a Target and Regulator of Epigenetic Mechanisms in Nonalcoholic Fatty Liver Disease. Cells 2023; 12:1205. [PMID: 37190114 PMCID: PMC10136748 DOI: 10.3390/cells12081205] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/11/2023] [Revised: 04/17/2023] [Accepted: 04/19/2023] [Indexed: 05/17/2023] Open
Abstract
Peroxisome proliferator-activated receptor-γ (PPARγ) belongs to the superfamily of nuclear receptors that control the transcription of multiple genes. Although it is found in many cells and tissues, PPARγ is mostly expressed in the liver and adipose tissue. Preclinical and clinical studies show that PPARγ targets several genes implicated in various forms of chronic liver disease, including nonalcoholic fatty liver disease (NAFLD). Clinical trials are currently underway to investigate the beneficial effects of PPARγ agonists on NAFLD/nonalcoholic steatohepatitis. Understanding PPARγ regulators may therefore aid in unraveling the mechanisms governing the development and progression of NAFLD. Recent advances in high-throughput biology and genome sequencing have greatly facilitated the identification of epigenetic modifiers, including DNA methylation, histone modifiers, and non-coding RNAs as key factors that regulate PPARγ in NAFLD. In contrast, little is still known about the particular molecular mechanisms underlying the intricate relationships between these events. The paper that follows outlines our current understanding of the crosstalk between PPARγ and epigenetic regulators in NAFLD. Advances in this field are likely to aid in the development of early noninvasive diagnostics and future NAFLD treatment strategies based on PPARγ epigenetic circuit modification.
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Affiliation(s)
- Mohamed Zaiou
- Institut Jean-Lamour, Université de Lorraine, UMR 7198 CNRS, 54505 Vandoeuvre-les-Nancy, France
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22
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Yang Z, Wang L. Current, emerging, and potential therapies for non-alcoholic steatohepatitis. Front Pharmacol 2023; 14:1152042. [PMID: 37063264 PMCID: PMC10097909 DOI: 10.3389/fphar.2023.1152042] [Citation(s) in RCA: 14] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2023] [Accepted: 03/20/2023] [Indexed: 03/31/2023] Open
Abstract
Non-alcoholic fatty liver disease (NAFLD) has been identified as the most common chronic liver disease worldwide, with a growing incidence. NAFLD is considered the hepatic manifestation of a metabolic syndrome that emerges from multiple factors (e.g., oxidative stress, metabolic disorders, endoplasmic reticulum stress, cell death, and inflammation). Non-alcoholic steatohepatitis (NASH), an advanced form of NAFLD, has been reported to be a leading cause of cirrhosis and hepatic carcinoma, and it is progressing rapidly. Since there is no approved pharmacotherapy for NASH, a considerable number of therapeutic targets have emerged with the deepening of the research on NASH pathogenesis. In this study, the therapeutic potential and properties of regulating metabolism, the gut microbiome, antioxidant, microRNA, inhibiting apoptosis, targeting ferroptosis, and stem cell-based therapy in NASH are reviewed and evaluated. Since the single-drug treatment of NASH is affected by individual heterogeneous responses and side effects, it is imperative to precisely carry out targeted therapy with low toxicity. Lastly, targeted therapeutic agent delivery based on exosomes is proposed in this study, such that drugs with different mechanisms can be incorporated to generate high-efficiency and low-toxicity individualized medicine.
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Affiliation(s)
| | - Lin Wang
- Department of Hepatobiliary Surgery, Xi-Jing Hospital, The Fourth Military Medical University, Xi’an, China
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23
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Chen H, Tan H, Wan J, Zeng Y, Wang J, Wang H, Lu X. PPAR-γ signaling in nonalcoholic fatty liver disease: Pathogenesis and therapeutic targets. Pharmacol Ther 2023; 245:108391. [PMID: 36963510 DOI: 10.1016/j.pharmthera.2023.108391] [Citation(s) in RCA: 90] [Impact Index Per Article: 45.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/15/2023] [Revised: 03/20/2023] [Accepted: 03/20/2023] [Indexed: 03/26/2023]
Abstract
Non-alcoholic fatty liver disease (NAFLD), currently the leading cause of global chronic liver disease, has emerged as a major public health problem, more efficient therapeutics of which are thus urgently needed. Peroxisome proliferator-activated receptor γ (PPAR-γ), ligand-activated transcription factors of the nuclear hormone receptor superfamily, is considered a crucial metabolic regulator of hepatic lipid metabolism and inflammation. The role of PPAR-γ in the pathogenesis of NAFLD is gradually being recognized. Here, we outline the involvement of PPAR-γ in the pathogenesis of NAFLD through adipogenesis, insulin resistance, inflammation, oxidative stress, endoplasmic reticulum stress, and fibrosis. In addition, the evidence for PPAR-γ- targeted therapy for NAFLD are summarized. Altogether, PPAR-γ is a promising therapeutic target for NAFLD, and the development of drugs that can balance the beneficial and undesirable effects of PPAR-γ will bring new light to NAFLD patients.
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Affiliation(s)
- Hao Chen
- Department of Liver Surgery and Laboratory of Liver Surgery, West China Hospital, Sichuan University, Chengdu, China
| | - Huabing Tan
- Department of Infectious Diseases, Liver Disease Laboratory, Renmin Hospital, Hubei University of Medicine, Shiyan, Hubei, China
| | - Juan Wan
- West China Center of Excellence for Pancreatitis, Institute of Integrated Traditional Chinese and Western Medicine / West China School of Nursing, Sichuan University, Chengdu, China
| | - Yong Zeng
- Department of Liver Surgery and Laboratory of Liver Surgery, West China Hospital, Sichuan University, Chengdu, China
| | - Jincheng Wang
- Department of General Surgery, Liver Transplantation Center, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu, China
| | - Haichuan Wang
- Department of Liver Surgery and Laboratory of Liver Surgery, West China Hospital, Sichuan University, Chengdu, China; Department of Bioengineering and Therapeutic Sciences and Liver Center, University of California, San Francisco, CA, USA.
| | - Xiaojie Lu
- Department of General Surgery, Liver Transplantation Center, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu, China.
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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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25
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Harrison SA, Thang C, Bolze S, Dewitt S, Hallakou-Bozec S, Dubourg J, Bedossa P, Cusi K, Ratziu V, Grouin JM, Moller DE, Fouqueray P. Evaluation of PXL065 - deuterium-stabilized (R)-pioglitazone in patients with NASH: A phase II randomized placebo-controlled trial (DESTINY-1). J Hepatol 2023; 78:914-925. [PMID: 36804402 DOI: 10.1016/j.jhep.2023.02.004] [Citation(s) in RCA: 39] [Impact Index Per Article: 19.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/24/2022] [Revised: 01/19/2023] [Accepted: 02/01/2023] [Indexed: 02/23/2023]
Abstract
BACKGROUND & AIMS Pioglitazone (Pio) is efficacious in NASH, but its utility is limited by PPARγ-driven side effects. Pio is a mixture of two enantiomers (R, S). PXL065, deuterium-stabilized R-Pio, lacks PPARγ activity but retains non-genomic activity. We tested the hypothesis that PXL065 would have similar efficacy but a better safety profile than Pio in patients with NASH. METHODS Patients (≥8% liver fat, NAFLD activity score [NAS] ≥4, F1-F3) received daily doses of PXL065 (7.5, 15, 22.5 mg) or placebo 1:1:1:1 for 36 weeks. The primary endpoint was relative % change in liver fat content (LFC) on MRI-proton density fat fraction; liver histology, non-invasive tests, safety-tolerability, and pharmacokinetics were also assessed. RESULTS One hundred and seventeen patients were evaluated. All PXL065 groups met the primary endpoint (-21 to (-25% LFC, p = 0.008-0.02 vs. placebo); 40% (22.5 mg) achieved a ≥30% LFC reduction. Favorable trends in non-invasive tests including reductions in PIIINP (p = 0.02, 22.5 mg) and NAFLD fibrosis score (p = 0.04, 22.5 mg) were observed. On histology (n = 92), a ≥1 stage fibrosis improvement occurred in 40% (7.5 mg), 50% (15 mg, p = 0.06), and 35% (22.5 mg) vs. 17% for placebo; up to 50% of PXL065-treated patients achieved a ≥2 point NAS improvement without fibrosis worsening vs. 30% with placebo. Metabolic improvements included: HbA1c (-0.41% p = 0.003) and insulin sensitivity (HOMA-IR, p = 0.04; Adipo-IR, p = 0.002). Adiponectin increased (+114%, 22.5 mg, p <0.0001) vs. placebo. There was no dose-dependent effect on body weight or PXL065-related peripheral oedema signal. Overall, PXL065 was safe and well tolerated. Pharmacokinetics confirmed dose-proportional and higher steady state R- vs. S-Pio exposure. IMPACT AND IMPLICATIONS Pioglitazone (Pio) is an approved diabetes medicine with proven efficacy in non-alcoholic steatohepatitis (NASH); PXL065 is a novel related oral agent which has been shown to retain Pio's efficacy in preclinical NASH models, with reduced potential for PPARγ-driven side effects. Results of this phase II study are important as PXL065 improved several key NASH disease features with a favorable safety profile - these findings can be applied by researchers seeking to understand pathophysiology and to develop new therapies. These results also indicate that PXL065 warrants further clinical testing in a pivotal NASH trial. Other implications include the potential future availability of a distinct oral therapy for NASH that may be relevant for patients, providers and caregivers seeking to prevent the progression and complications of this disease. CONCLUSIONS PXL065 is a novel molecule which retains an efficacy profile in NASH similar to Pio with reduced potential for PPARγ-driven side effects. A pivotal clinical trial is warranted to confirm the histological benefits reported herein. IMPACT AND IMPLICATIONS Pioglitazone (Pio) is an approved diabetes medicine with proven efficacy in non-alcoholic steatohepatitis (NASH); PXL065 is a novel related oral agent which has been shown to retain Pio's efficacy in preclinical NASH models, with reduced potential for PPARγ-driven side effects. Results of this phase II study are important as PXL065 improved several key NASH disease features with a favorable safety profile - these findings can be applied by researchers seeking to understand pathophysiology and to develop new therapies. These results also indicate that PXL065 warrants further clinical testing in a pivotal NASH trial. Other implications include the potential future availability of a distinct oral therapy for NASH that may be relevant for patients, providers and caregivers seeking to prevent the progression and complications of this disease.
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Affiliation(s)
| | | | | | | | | | | | | | - Kenneth Cusi
- Division of Endocrinology, Diabetes and Metabolism, University of Florida, Gainesville, FL, USA
| | - Vlad Ratziu
- Sorbonne Université, ICAN, Hospital Pitié-Salpêtrière, INSERM UMRS 1138 CRC, Paris, France
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Sessa L, Concilio S, Fominaya J, Eletto D, Piotto S, Busquets X. A new serotonin 2A receptor antagonist with potential benefits in Non-Alcoholic Fatty Liver Disease. Life Sci 2023; 314:121315. [PMID: 36581095 DOI: 10.1016/j.lfs.2022.121315] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/23/2022] [Revised: 12/16/2022] [Accepted: 12/18/2022] [Indexed: 12/28/2022]
Abstract
Peripheral 5-hydroxytryptamine 2A receptor (5-HT2AR) could be a new pharmacological target for NASH, an evolution of NAFLD characterized by hepatic steatosis, cytoskeletal alterations, and hepatic inflammation that can arise with or without fibrosis. SJT4a is a synthetic β-carboline antagonist for 5-HT2AR developed by SJT molecular research to treat NASH. We performed a combined in silico/in vivo study on this potential drug to elucidate its activity and possible mechanism of action. The in silico protocol compares SJT4a with four known 5-HT2AR ligands with different activities (LSD, methiothepin, zotepine, risperidone). We performed molecular docking calculations, evaluation of binding energy by AI-based methods and Molecular Dynamics simulations of the five ligand-target complexes. Moreover, we used a pseudo-semantic analysis to evaluate the potential mechanism of action of SJT4a. In silico predictions and pseudo-semantic analysis suggested antagonistic activity for SJT4a. The in silico prediction was confirmed by [3H]-5HT radioligand binding together with SJT4a competition analysis in CHO-K1 cell cultures expressing 5-HT2AR. SJT4a was then tested in vivo. We investigated the effect of 8 weeks of treatment with SJT4A on metabolic parameters, liver pathology, NAFLD activity score, and fibrosis stage in male DIO-NASH C57BL/6 J mice diet-induced obesity fed with an obesogenic diet compared with DIO-NASH and LEAN-CHOW vehicles. In our tests, SJT4a showed intense activity in diminishing the most relevant hallmarks of NASH in the DIO-NASH mice model. We proposed a possible mode of action for SJT4a based on its 5-HT2AR antagonist activity.
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Affiliation(s)
- Lucia Sessa
- Department of Pharmacy, University of Salerno, Via Giovanni Paolo II, 132, Fisciano 84084, SA, Italy; Bionam Center for Biomaterials, University of Salerno, Via Giovanni Paolo II, 132, Fisciano 84084, SA, Italy
| | - Simona Concilio
- Department of Pharmacy, University of Salerno, Via Giovanni Paolo II, 132, Fisciano 84084, SA, Italy; Bionam Center for Biomaterials, University of Salerno, Via Giovanni Paolo II, 132, Fisciano 84084, SA, Italy
| | - Jesús Fominaya
- Laboratory of Molecular Cell Biomedicine, Department of Biology, University of the Balearic Islands, 07122 Palma, Spain
| | - Daniela Eletto
- Department of Pharmacy, University of Salerno, Via Giovanni Paolo II, 132, Fisciano 84084, SA, Italy
| | - Stefano Piotto
- Department of Pharmacy, University of Salerno, Via Giovanni Paolo II, 132, Fisciano 84084, SA, Italy; Bionam Center for Biomaterials, University of Salerno, Via Giovanni Paolo II, 132, Fisciano 84084, SA, Italy.
| | - Xavier Busquets
- Laboratory of Molecular Cell Biomedicine, Department of Biology, University of the Balearic Islands, 07122 Palma, Spain.
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27
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Lee SM, Muratalla J, Karimi S, Diaz-Ruiz A, Frutos MD, Guzman G, Ramos-Molina B, Cordoba-Chacon J. Hepatocyte PPARγ contributes to the progression of non-alcoholic steatohepatitis in male and female obese mice. Cell Mol Life Sci 2023; 80:39. [PMID: 36629912 PMCID: PMC10082675 DOI: 10.1007/s00018-022-04629-z] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2022] [Revised: 10/14/2022] [Accepted: 11/10/2022] [Indexed: 01/12/2023]
Abstract
Non-alcoholic steatohepatitis (NASH) is associated with obesity and increased expression of hepatic peroxisome proliferator-activated receptor γ (PPARγ). However, the relevance of hepatocyte PPARγ in NASH associated with obesity is still poorly understood. In this study, hepatocyte PPARγ was knocked out (PpargΔHep) in male and female mice after the development of high-fat diet-induced obesity. The diet-induced obese mice were then maintained on their original diet or switched to a high fat, cholesterol, and fructose (HFCF) diet to induce NASH. Hepatic PPARγ expression was mostly derived from hepatocytes and increased by high fat diets. PpargΔHep reduced HFCF-induced NASH progression without altering steatosis, reduced the expression of key genes involved in hepatic fibrosis in HFCF-fed male and female mice, and decreased the area of collagen-stained fibrosis in the liver of HFCF-fed male mice. Moreover, transcriptomic and metabolomic data suggested that HFCF-diet regulated hepatic amino acid metabolism in a hepatocyte PPARγ-dependent manner. PpargΔHep increased betaine-homocysteine s-methyltransferase expression and reduced homocysteine levels in HFCF-fed male mice. In addition, in a cohort of 102 obese patients undergoing bariatric surgery with liver biopsies, 16 cases were scored with NASH and were associated with increased insulin resistance and hepatic PPARγ expression. Our study shows that hepatocyte PPARγ expression is associated with NASH in mice and humans. In male mice, hepatocyte PPARγ negatively regulates methionine metabolism and contributes to the progression of fibrosis.
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Affiliation(s)
- Samuel M Lee
- Division of Endocrinology, Diabetes and Metabolism, Department of Medicine, University of Illinois at Chicago, 835 S. Wolcott Ave (North Entrance) Suite E625, M/C 640, Chicago, IL, USA
| | - Jose Muratalla
- Division of Endocrinology, Diabetes and Metabolism, Department of Medicine, University of Illinois at Chicago, 835 S. Wolcott Ave (North Entrance) Suite E625, M/C 640, Chicago, IL, USA
| | - Saman Karimi
- Department of Pathology, University of Illinois at Chicago, Chicago, IL, USA
| | | | - Maria Dolores Frutos
- Department of General and Digestive System Surgery, Virgen de La Arrixaca University Hospital, Murcia, Spain
| | - Grace Guzman
- Department of Pathology, University of Illinois at Chicago, Chicago, IL, USA
| | - Bruno Ramos-Molina
- Obesity and Metabolism Group, Biomedical Research Institute of Murcia (IMIB), Murcia, Spain
| | - Jose Cordoba-Chacon
- Division of Endocrinology, Diabetes and Metabolism, Department of Medicine, University of Illinois at Chicago, 835 S. Wolcott Ave (North Entrance) Suite E625, M/C 640, Chicago, IL, USA.
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28
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Marie S, Frost KL, Hau RK, Martinez-Guerrero L, Izu JM, Myers CM, Wright SH, Cherrington NJ. Predicting disruptions to drug pharmacokinetics and the risk of adverse drug reactions in non-alcoholic steatohepatitis patients. Acta Pharm Sin B 2023; 13:1-28. [PMID: 36815037 PMCID: PMC9939324 DOI: 10.1016/j.apsb.2022.08.018] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/24/2022] [Revised: 07/29/2022] [Accepted: 08/03/2022] [Indexed: 12/18/2022] Open
Abstract
The liver plays a central role in the pharmacokinetics of drugs through drug metabolizing enzymes and transporters. Non-alcoholic steatohepatitis (NASH) causes disease-specific alterations to the absorption, distribution, metabolism, and excretion (ADME) processes, including a decrease in protein expression of basolateral uptake transporters, an increase in efflux transporters, and modifications to enzyme activity. This can result in increased drug exposure and adverse drug reactions (ADRs). Our goal was to predict drugs that pose increased risks for ADRs in NASH patients. Bibliographic research identified 71 drugs with reported ADRs in patients with liver disease, mainly non-alcoholic fatty liver disease (NAFLD), 54 of which are known substrates of transporters and/or metabolizing enzymes. Since NASH is the progressive form of NAFLD but is most frequently undiagnosed, we identified other drugs at risk based on NASH-specific alterations to ADME processes. Here, we present another list of 71 drugs at risk of pharmacokinetic disruption in NASH, based on their transport and/or metabolism processes. It encompasses drugs from various pharmacological classes for which ADRs may occur when used in NASH patients, especially when eliminated through multiple pathways altered by the disease. Therefore, these results may inform clinicians regarding the selection of drugs for use in NASH patients.
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Affiliation(s)
- Solène Marie
- College of Pharmacy, Department of Pharmacology & Toxicology, University of Arizona, Tucson, AZ 85721, USA
| | - Kayla L. Frost
- College of Pharmacy, Department of Pharmacology & Toxicology, University of Arizona, Tucson, AZ 85721, USA
| | - Raymond K. Hau
- College of Pharmacy, Department of Pharmacology & Toxicology, University of Arizona, Tucson, AZ 85721, USA
| | - Lucy Martinez-Guerrero
- College of Pharmacy, Department of Pharmacology & Toxicology, University of Arizona, Tucson, AZ 85721, USA
| | - Jailyn M. Izu
- College of Pharmacy, Department of Pharmacology & Toxicology, University of Arizona, Tucson, AZ 85721, USA
| | - Cassandra M. Myers
- College of Pharmacy, Department of Pharmacology & Toxicology, University of Arizona, Tucson, AZ 85721, USA
| | - Stephen H. Wright
- College of Medicine, Department of Physiology, University of Arizona, Tucson, AZ 85724, USA
| | - Nathan J. Cherrington
- College of Pharmacy, Department of Pharmacology & Toxicology, University of Arizona, Tucson, AZ 85721, USA,Corresponding author. Tel.: +1 520 6260219; fax: +1 520 6266944.
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Liu L, Zhou Y, Liu Z, Li J, Hu L, He L, Gao G, Kidd B, Walsh A, Jiang R, Wu C, Zhang K, Xie L. Osr1 Regulates Macrophage-mediated Liver Inflammation in Nonalcoholic Fatty Liver Disease Progression. Cell Mol Gastroenterol Hepatol 2022; 15:1117-1133. [PMID: 36581078 PMCID: PMC10036739 DOI: 10.1016/j.jcmgh.2022.12.010] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/28/2022] [Revised: 12/16/2022] [Accepted: 12/16/2022] [Indexed: 12/31/2022]
Abstract
BACKGROUND & AIMS Liver macrophage-mediated inflammation contributes to the pathogenesis of the nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH). Odd skipped-related 1 (Osr1) is a putative transcription factor previously reported to be involved in NASH progression; however, the underlying mechanisms remain unknown. The current study focused on the role of Osr1 in macrophage polarization and metabolism and its associated functions in the inflammation-induced pathogenesis of NASH. METHODS OSR1/Osr1 expression patterns were compared in normal and NASH patients and mouse livers. NASH was established and compared between hepatocyte-specific Osr1 knockout (Osr1ΔHep), macrophage-specific Osr1 knockout (Osr1ΔMφ), and wild-type (Osr1F) mice fed with 3 different chronic obesogenic diets and methionine choline-deficient diet. Using genetic and therapeutic strategies in vitro and in vivo, the downstream targets of Osr1 and the associated mechanisms in inflammation-induced NASH were established. RESULTS Osr1 was expressed in both hepatocytes and macrophages and exhibited different expression patterns in NASH. In NAFLD and NASH murine models, deleting Osr1 in myeloid cells (Osr1ΔMφ), but not hepatocytes, aggravated steatohepatitis with pronounced liver inflammation. Myeloid Osr1 deletion resulted in a polarization switch toward a pro-inflammatory phenotype associated with reduced oxidative phosphorylation activity. These inflamed Osr1ΔMφ macrophages promoted steatosis and inflammation in hepatocytes via cytokine secretion. We identified 2 downstream transcriptional targets of Osr1, c-Myc, and PPARγ and established the Osr1-PPARγ cascade in macrophage polarization and liver inflammation by genetic study and rosiglitazone treatment in vivo. We tested a promising intervention strategy targeting Osr1-PPARγ by AAV8L-delivered Osr1 expression or rosiglitazone that significantly repressed NAFLD/NASH progression in Osr1F and Osr1ΔMφ mice. CONCLUSIONS Myeloid Osr1 mediates liver immune homeostasis and disrupting Osr1 aggravates the progression of NAFLD/NASH.
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Affiliation(s)
- Lin Liu
- Department of Nutrition, Texas A&M University, College Station, Texas
| | - Yi Zhou
- Tongji Hospital, Huazhong University of Science and Technology, Wuhan, Hubei, China
| | - Zhimin Liu
- Department of Nutrition, Texas A&M University, College Station, Texas
| | - Jiangyuan Li
- Department of Statistics, Texas A&M University, College Station, Texas; Institute of Biosciences & Technology, Texas A&M University, Houston, Texas
| | - Linghao Hu
- Department of Biomedical Engineering, Texas A&M University, College Station, Texas
| | - Leya He
- Department of Nutrition, Texas A&M University, College Station, Texas
| | - Guannan Gao
- Department of Statistics, Texas A&M University, College Station, Texas; Institute of Biosciences & Technology, Texas A&M University, Houston, Texas
| | - Brian Kidd
- Department of Statistics, Texas A&M University, College Station, Texas; Institute of Biosciences & Technology, Texas A&M University, Houston, Texas
| | - Alexandra Walsh
- Department of Biomedical Engineering, Texas A&M University, College Station, Texas
| | - Rulang Jiang
- Division of Developmental Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio
| | - Chaodong Wu
- Department of Nutrition, Texas A&M University, College Station, Texas
| | - Ke Zhang
- Department of Nutrition, Texas A&M University, College Station, Texas; Institute of Biosciences & Technology, Texas A&M University, Houston, Texas
| | - Linglin Xie
- Department of Nutrition, Texas A&M University, College Station, Texas.
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Alwadani AH, Almasri SA, Aloud AA, Albadr NA, Alshammari GM, Yahya MA. The Synergistic Protective Effect of γ-Oryzanol (OZ) and N-Acetylcysteine (NAC) against Experimentally Induced NAFLD in Rats Entails Hypoglycemic, Antioxidant, and PPARα Stimulatory Effects. Nutrients 2022; 15:nu15010106. [PMID: 36615764 PMCID: PMC9823776 DOI: 10.3390/nu15010106] [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] [Subscribe] [Scholar Register] [Received: 12/04/2022] [Revised: 12/21/2022] [Accepted: 12/22/2022] [Indexed: 12/28/2022] Open
Abstract
This study estimated that the combined effect of γ-Oryzanol and N-acetylcysteine (NAC) against high-fat diet (HFD)-induced non-alcoholic fatty liver disease (NAFLD) in rats also estimated some of their mechanisms of action. Adult male rats were divided into seven groups (n = 8 each) as control, control + NAC, control + γ-Oryzanol, HFD, HFD + NAC, HFD + γ-Oryzanol, and HFD + NAC + γ-Oryzanol. NAC was administered orally at a final concentration of 200 mg/kg, whereas γ-Oryzanol was added to diets at a concentration of 0.16. All treatments were conducted for 17 weeks and daily. Both NAC and γ-Oryzanol were able to reduce final body weights, fat weights, fasting glucose, fasting insulin, serum, and serum levels of liver function enzymes as well as the inflammatory markers such as tumor necrosis factor-α (TNF-α), interleukine-6 (IL-6), and leptin in HFD-fed rats. They also improved hepatic structure and glucose tolerance, increased adiponectin levels, and reduced serum and hepatic levels of triglycerides (TGs) and cholesterol (CHOL) in these rats. These effects were concomitant with a reduction in the hepatic levels of lipid peroxides (MDA) and serum levels of LDL-C, but also with an increment in the hepatic levels of superoxide dismutase (SOD) and glutathione (GSH). Interestingly, only treatment with γ-Oryzanol stimulated the mRNA levels of proliferator-activated receptor alpha (PPARα) and carnitine palmitoyltransferase 1 (CPT1) in the liver and white adipose tissue (WAT) of rats. Of note, the combination therapy of both drugs resulted in maximum effects and restored almost normal liver structure and basal levels of all the above-mentioned metabolic parameters. In conclusion, a combination therapy of γ-Oryzanol and NAC is an effective therapy to treat NAFLD, which can act via several mechanisms on the liver and adipose tissue.
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Affiliation(s)
- Ashwag H. Alwadani
- Department of of Food Science and Nutrition, College of Food and Agricultural Sciences, King Saud University, Riyadh 11451, Saudi Arabia
- Department of Home Economics, University College in Farasan, Jazan University, Jazan 54943, Saudi Arabia
| | - Soheir A. Almasri
- Department of of Food Science and Nutrition, College of Food and Agricultural Sciences, King Saud University, Riyadh 11451, Saudi Arabia
- Correspondence:
| | - Amal A. Aloud
- Department of of Food Science and Nutrition, College of Food and Agricultural Sciences, King Saud University, Riyadh 11451, Saudi Arabia
| | - Nawal A. Albadr
- Department of of Food Science and Nutrition, College of Food and Agricultural Sciences, King Saud University, Riyadh 11451, Saudi Arabia
| | - Ghedeir M. Alshammari
- Department of of Food Science and Nutrition, College of Food and Agricultural Sciences, King Saud University, Riyadh 11451, Saudi Arabia
| | - Mohammed Abdo Yahya
- Department of of Food Science and Nutrition, College of Food and Agricultural Sciences, King Saud University, Riyadh 11451, Saudi Arabia
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Promising hepatoprotective effects of lycopene in different liver diseases. Life Sci 2022; 310:121131. [PMID: 36306869 DOI: 10.1016/j.lfs.2022.121131] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/10/2022] [Revised: 10/13/2022] [Accepted: 10/23/2022] [Indexed: 11/07/2022]
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Honda A, Ishii I. The Perspective of PPAR Dual/Pan Agonists as Therapeutic Drugs against NAFLD. YAKUGAKU ZASSHI 2022; 142:1335-1343. [DOI: 10.1248/yakushi.22-00159-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/04/2022]
Affiliation(s)
- Akihiro Honda
- Laboratory of Health Chemistry, Showa Pharmaceutical University
| | - Isao Ishii
- Laboratory of Health Chemistry, Showa Pharmaceutical University
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Yan M, Man S, Ma L, Gao W. Comprehensive molecular mechanisms and clinical therapy in nonalcoholic steatohepatitis: An overview and current perspectives. Metabolism 2022; 134:155264. [PMID: 35810782 DOI: 10.1016/j.metabol.2022.155264] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/18/2022] [Revised: 06/28/2022] [Accepted: 07/04/2022] [Indexed: 10/17/2022]
Abstract
Our understanding of nonalcoholic steatohepatitis (NASH) pathophysiology continues to advance rapidly. Given the complexity of the pathogenesis of NASH, the field has moved from describing the single pathogenesis of NASH to deeply phenotyping with a description of the multi-mechanism and multi-target pathogenesis that includes glucose, lipid and cholesterol metabolism, fibrotic progression, inflammation, immune reaction and apoptosis. To make the picture more complex, the pathogenesis of NASH involves pathological connections between the liver and several organs such as the adipose, pancreas, kidney and gut. Numerous pharmacologic candidates have been tested in clinical trials and have generated some positive results. Importantly, PPAR as triglyceride synthesis inhibitor and FXR as bile acids synthesis inhibitor have displayed beneficial effects on candidates for lipid and cholesterol metabolism. Although the efficacy of these drugs has been affirmed, serious side effects hinder their further development. It is a particularly important task to carry out the in-depth long-term research. Additionally, drug combination increases response rate and reduces side effects of a single drug. Mastering the advantages and limitations of clinical candidate drugs and continuous improvement and innovation are necessary to formulate a new strategy for the future treatment of NASH.
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Affiliation(s)
- Mengyao Yan
- State Key Laboratory of Food Nutrition and Safety, Key Laboratory of Industrial Microbiology, Ministry of Education, Tianjin Key Laboratory of Industry Microbiology, National and Local United Engineering Lab of Metabolic Control Fermentation Technology, China International Science and Technology Cooperation Base of Food Nutrition/Safety and Medicinal Chemistry, College of Biotechnology, Tianjin University of Science & Technology, Tianjin 300457, China
| | - Shuli Man
- State Key Laboratory of Food Nutrition and Safety, Key Laboratory of Industrial Microbiology, Ministry of Education, Tianjin Key Laboratory of Industry Microbiology, National and Local United Engineering Lab of Metabolic Control Fermentation Technology, China International Science and Technology Cooperation Base of Food Nutrition/Safety and Medicinal Chemistry, College of Biotechnology, Tianjin University of Science & Technology, Tianjin 300457, China.
| | - Long Ma
- State Key Laboratory of Food Nutrition and Safety, Key Laboratory of Industrial Microbiology, Ministry of Education, Tianjin Key Laboratory of Industry Microbiology, National and Local United Engineering Lab of Metabolic Control Fermentation Technology, China International Science and Technology Cooperation Base of Food Nutrition/Safety and Medicinal Chemistry, College of Biotechnology, Tianjin University of Science & Technology, Tianjin 300457, China.
| | - Wenyuan Gao
- Tianjin Key Laboratory for Modern Drug Delivery & High-Efficiency, School of Pharmaceutical Science and Technology, Tianjin University, Weijin Road, Tianjin 300072, China.
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Takeshita Y, Honda M, Harada K, Kita Y, Takata N, Tsujiguchi H, Tanaka T, Goto H, Nakano Y, Iida N, Arai K, Yamashita T, Mizukoshi E, Nakamura H, Kaneko S, Takamura T. Comparison of Tofogliflozin and Glimepiride Effects on Nonalcoholic Fatty Liver Disease in Participants With Type 2 Diabetes: A Randomized, 48-Week, Open-Label, Active-Controlled Trial. Diabetes Care 2022; 45:2064-2075. [PMID: 35894933 PMCID: PMC9472500 DOI: 10.2337/dc21-2049] [Citation(s) in RCA: 62] [Impact Index Per Article: 20.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/01/2021] [Accepted: 05/21/2022] [Indexed: 02/03/2023]
Abstract
OBJECTIVE Nonalcoholic fatty liver disease (NAFLD) is a liver phenotype of type 2 diabetes and obesity. Currently, the efficacy of sodium-glucose cotransporter 2 (SGLT2) inhibitors and sulfonylureas in liver pathology and hepatic gene expression profiles for type 2 diabetes with NAFLD are unknown. RESEARCH DESIGN AND METHODS We conducted a 48 week, randomized, open-label, parallel-group trial involving participants with biopsy-confirmed NAFLD. A total of 40 participants were randomly assigned to receive once daily 20 mg tofogliflozin or 0.5 mg glimepiride. The primary outcome was the percentage of participants with at least an improvement in all individual scores for histological categories of steatosis, hepatocellular ballooning, lobular inflammation, and fibrosis by at least 1 point. The secondary end points were the changes in liver enzymes, metabolic markers, and hepatic gene expression profiles. RESULTS Fibrosis scores improved in the tofogliflozin group (60%, P = 0.001), whereas the change from baseline did not differ significantly between the groups (P = 0.172). The histological variables of steatosis (65%, P = 0.001), hepatocellular ballooning (55%, P = 0.002), and lobular inflammation (50%, P = 0.003) were improved in the tofogliflozin group, whereas only hepatocellular ballooning was improved in the glimepiride group (25%, P = 0.025). Hepatic gene expression profiling revealed histology-associated signatures in energy metabolism, inflammation, and fibrosis that were reversed with tofogliflozin. CONCLUSIONS Tofogliflozin and, to a lesser degree, glimepiride led to liver histological and metabolic improvement in participants with type 2 diabetes and NAFLD, with no significant difference between the agents. The hepatic expression of the genes involved in energy metabolism, inflammation, and fibrosis was well correlated with liver histological changes and rescued by tofogliflozin. We need further confirmation through long-term larger-scale clinical trials of SGLT2 inhibitors.
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Affiliation(s)
- Yumie Takeshita
- Department of Endocrinology and Metabolism, Graduate School of Medical Sciences, Kanazawa University, Kanazawa, Ishikawa, Japan
| | - Masao Honda
- Department of Gastroenterology, Graduate School of Medical Sciences, Kanazawa University Kanazawa, Ishikawa, Japan
| | - Kenichi Harada
- Department of Human Pathology, Graduate School of Medical Sciences, Kanazawa University, Kanazawa, Ishikawa, Japan
| | - Yuki Kita
- Department of Endocrinology and Metabolism, Graduate School of Medical Sciences, Kanazawa University, Kanazawa, Ishikawa, Japan
| | - Noboru Takata
- Department of Gastroenterology, Graduate School of Medical Sciences, Kanazawa University Kanazawa, Ishikawa, Japan
| | - Hiromasa Tsujiguchi
- Department of Environmental and Preventive Medicine, Faculty of Medicine, Institute of Medical, Pharmaceutical and Health Sciences, Kanazawa University, Kanazawa, Ishikawa, Japan
| | - Takeo Tanaka
- Department of Endocrinology and Metabolism, Graduate School of Medical Sciences, Kanazawa University, Kanazawa, Ishikawa, Japan
| | - Hisanori Goto
- Department of Endocrinology and Metabolism, Graduate School of Medical Sciences, Kanazawa University, Kanazawa, Ishikawa, Japan
| | - Yujiro Nakano
- Department of Endocrinology and Metabolism, Graduate School of Medical Sciences, Kanazawa University, Kanazawa, Ishikawa, Japan
| | - Noriho Iida
- Department of Gastroenterology, Graduate School of Medical Sciences, Kanazawa University Kanazawa, Ishikawa, Japan
| | - Kuniaki Arai
- Department of Gastroenterology, Graduate School of Medical Sciences, Kanazawa University Kanazawa, Ishikawa, Japan
| | - Tatsuya Yamashita
- Department of Gastroenterology, Graduate School of Medical Sciences, Kanazawa University Kanazawa, Ishikawa, Japan
| | - Eishiro Mizukoshi
- Department of Gastroenterology, Graduate School of Medical Sciences, Kanazawa University Kanazawa, Ishikawa, Japan
| | - Hiroyuki Nakamura
- Department of Environmental and Preventive Medicine, Faculty of Medicine, Institute of Medical, Pharmaceutical and Health Sciences, Kanazawa University, Kanazawa, Ishikawa, Japan
| | - Shuichi Kaneko
- Department of Gastroenterology, Graduate School of Medical Sciences, Kanazawa University Kanazawa, Ishikawa, Japan
| | - Toshinari Takamura
- Department of Endocrinology and Metabolism, Graduate School of Medical Sciences, Kanazawa University, Kanazawa, Ishikawa, Japan
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Adipokines in Non-Alcoholic Fatty Liver Disease: Are We on the Road toward New Biomarkers and Therapeutic Targets? BIOLOGY 2022; 11:biology11081237. [PMID: 36009862 PMCID: PMC9405285 DOI: 10.3390/biology11081237] [Citation(s) in RCA: 35] [Impact Index Per Article: 11.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 07/19/2022] [Revised: 08/16/2022] [Accepted: 08/17/2022] [Indexed: 12/04/2022]
Abstract
Simple Summary Non-alcoholic fatty liver disease (NAFLD) is an unmet medical need due to its increasingly high incidence, severe clinical consequences, and the absence of feasible diagnostic tools and effective drugs. This review summarizes the preclinical and clinical data on adipokines, cytokine-like hormones secreted by adipose tissue, and NAFLD. The aim is to establish the potential of adipokines as diagnostic and prognostic biomarkers, as well as their potential as therapeutic targets for NAFLD. The limitations of current research are also discussed, and future perspectives are outlined. Abstract Non-alcoholic fatty liver disease (NAFLD) has become the major cause of chronic hepatic illness and the leading indication for liver transplantation in the future decades. NAFLD is also commonly associated with other high-incident non-communicable diseases, such as cardiovascular complications, type 2 diabetes, and chronic kidney disease. Aggravating the socio-economic impact of this complex pathology, routinely feasible diagnostic methodologies and effective drugs for NAFLD management are unavailable. The pathophysiology of NAFLD, recently defined as metabolic associated fatty liver disease (MAFLD), is correlated with abnormal adipose tissue–liver axis communication because obesity-associated white adipose tissue (WAT) inflammation and metabolic dysfunction prompt hepatic insulin resistance (IR), lipid accumulation (steatosis), non-alcoholic steatohepatitis (NASH), and fibrosis. Accumulating evidence links adipokines, cytokine-like hormones secreted by adipose tissue that have immunometabolic activity, with NAFLD pathogenesis and progression; however, much uncertainty still exists. Here, the current knowledge on the roles of leptin, adiponectin, ghrelin, resistin, retinol-binding protein 4 (RBP4), visfatin, chemerin, and adipocyte fatty-acid-binding protein (AFABP) in NAFLD, taken from preclinical to clinical studies, is overviewed. The effect of therapeutic interventions on adipokines’ circulating levels are also covered. Finally, future directions to address the potential of adipokines as therapeutic targets and disease biomarkers for NAFLD are discussed.
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Baumann A, Burger K, Brandt A, Staltner R, Jung F, Rajcic D, Lorenzo Pisarello MJ, Bergheim I. GW9662, a peroxisome proliferator-activated receptor gamma antagonist, attenuates the development of non-alcoholic fatty liver disease. Metabolism 2022; 133:155233. [PMID: 35654114 DOI: 10.1016/j.metabol.2022.155233] [Citation(s) in RCA: 31] [Impact Index Per Article: 10.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/03/2021] [Revised: 05/20/2022] [Accepted: 05/26/2022] [Indexed: 12/19/2022]
Abstract
BACKGROUND AND AIMS Insulin resistance is among the key risk factors for the development of non-alcoholic fatty liver disease (NAFLD). Recently, it has been reported that GW9662, shown to be a potent peroxisome proliferator-activated receptor gamma (PPARγ) antagonist, may improve insulin sensitivity in settings of type 2 diabetes. Here, we determined the effects of GW9662 on the development of NAFLD and molecular mechanisms involved. METHODS Female C57BL/6J mice were pair-fed either a liquid control diet (C) or a fat-, fructose- and cholesterol-rich diet (FFC) for 8 weeks while either being treated with GW9662 (1 mg/kg body weight; C+GW9662 and FFC+GW9662) or vehicle (C and FFC) i.p. three times weekly. Indices of liver damage and inflammation, parameters of glucose metabolism and portal endotoxin levels were determined. Lipopolysaccharide (LPS)-challenged J774A.1 cells were treated with 10 μM GW9662. RESULTS Despite similar caloric intake the development of NAFLD and insulin resistance were significantly attenuated in FFC+GW9662-treated mice when compared to FFC-fed animals. Bacterial endotoxin levels in portal plasma were almost similarly increased in both FFC-fed groups while expressions of toll-like receptor 4 (Tlr4), myeloid differentiation primary response 88 (Myd88) and interleukin 1 beta (Il1b) as well as nitrite (NO2-) concentration in liver were significantly higher in FFC-fed mice than in FFC+GW9662-treated animals. In J774A.1 cells, treatment with GW9662 significantly attenuated LPS-induced expression of Il1b, interleukin 6 (Il6) and inducible nitric oxide synthase (iNos) as well as NO2- formation. CONCLUSION In summary, our data suggest that the PPARγ antagonist GW9662 attenuates the development of a diet-induced NAFLD and that this is associated with a protection against the activation of the TLR4 signaling cascade.
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Affiliation(s)
- Anja Baumann
- Department of Nutritional Sciences, Molecular Nutritional Science, University of Vienna, Vienna, Austria
| | - Katharina Burger
- Department of Nutritional Sciences, Molecular Nutritional Science, University of Vienna, Vienna, Austria
| | - Annette Brandt
- Department of Nutritional Sciences, Molecular Nutritional Science, University of Vienna, Vienna, Austria
| | - Raphaela Staltner
- Department of Nutritional Sciences, Molecular Nutritional Science, University of Vienna, Vienna, Austria
| | - Finn Jung
- Department of Nutritional Sciences, Molecular Nutritional Science, University of Vienna, Vienna, Austria
| | - Dragana Rajcic
- Department of Nutritional Sciences, Molecular Nutritional Science, University of Vienna, Vienna, Austria
| | | | - Ina Bergheim
- Department of Nutritional Sciences, Molecular Nutritional Science, University of Vienna, Vienna, Austria.
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Katoch S, Sharma V, Patial V. Peroxisome proliferator-activated receptor gamma as a therapeutic target for hepatocellular carcinoma: Experimental and clinical scenarios. World J Gastroenterol 2022; 28:3535-3554. [PMID: 36161051 PMCID: PMC9372809 DOI: 10.3748/wjg.v28.i28.3535] [Citation(s) in RCA: 16] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/17/2022] [Revised: 04/25/2022] [Accepted: 06/24/2022] [Indexed: 02/06/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is the most common type of liver cancer worldwide. Viral hepatitis is a significant risk factor for HCC, although metabolic syndrome and diabetes are more frequently associated with the HCC. With increasing prevalence, there is expected to be > 1 million cases annually by 2025. Therefore, there is an urgent need to establish potential therapeutic targets to cure this disease. Peroxisome-proliferator-activated receptor gamma (PPARγ) is a ligand-activated transcription factor that plays a crucial role in the patho-physiology of HCC. Many synthetic agonists of PPARγ suppress HCC in experimental studies and clinical trials. These synthetic agonists have shown promising results by inducing cell cycle arrest and apoptosis in HCC cells and preventing the invasion and metastasis of HCC. However, some synthetic agonists also pose severe side effects in addition to their therapeutic efficacy. Thus natural PPARγ agonists can be an alternative to exploit this potential target for HCC treatment. In this review, the regulatory role of PPARγ in the pathogenesis of HCC is elucidated. Furthermore, the experimental and clinical scenario of both synthetic and natural PPARγ agonists against HCC is discussed. Most of the available literature advocates PPARγ as a potential therapeutic target for the treatment of HCC.
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Affiliation(s)
- Swati Katoch
- Division of Dietetics and Nutrition Technology, Institute of Himalayan Bioresource Technology, Palampur 176061, Himachal Pradesh, India
- Academy of Scientific and Innovative Research, Ghaziabad 201002, UP, India
| | - Vinesh Sharma
- Division of Dietetics and Nutrition Technology, Institute of Himalayan Bioresource Technology, Palampur 176061, Himachal Pradesh, India
- Academy of Scientific and Innovative Research, Ghaziabad 201002, UP, India
| | - Vikram Patial
- Division of Dietetics and Nutrition Technology, Institute of Himalayan Bioresource Technology, Palampur 176061, Himachal Pradesh, India
- Academy of Scientific and Innovative Research, Ghaziabad 201002, UP, India
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Combination Therapies for Nonalcoholic Fatty Liver Disease. J Pers Med 2022; 12:jpm12071166. [PMID: 35887662 PMCID: PMC9322793 DOI: 10.3390/jpm12071166] [Citation(s) in RCA: 31] [Impact Index Per Article: 10.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/04/2022] [Revised: 07/01/2022] [Accepted: 07/13/2022] [Indexed: 11/17/2022] Open
Abstract
Nonalcoholic fatty liver disease (NAFLD) is considered a highly prevalent disease associated with various co-morbidities that lead to socioeconomic burden. Despite large-scale investigation, no pharmacological treatment has been approved specifically for NAFLD to date. Lifestyle modifications and diet are regarded as highly beneficial for the management of NAFLD, albeit with poor compliance, thus rendering pharmacological treatment highly important. Based on the current failure to discover a “magic bullet” to treat all patients with NAFLD and considering the multifaceted pathophysiology of the disease, combination therapies may be considered to be a rational alternative approach. In this regard, several drug categories have been considered, including, but not limited to, lipid-lowering, anti-hypertensive, glucose-lowering, anti-obesity, anti-oxidant, anti-inflammatory and anti-fibrotic medications. The aim of this review is, in addition to summarizing some of the multiple factors contributing to the pathophysiology of NAFLD, to focus on the efficacy of pharmacological combinations on the management of NAFLD. This may provide evidence for a more personalized treatment of patients with NAFLD in the future.
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Vujkovic M, Ramdas S, Lorenz KM, Guo X, Darlay R, Cordell HJ, He J, Gindin Y, Chung C, Myers RP, Schneider CV, Park J, Lee KM, Serper M, Carr RM, Kaplan DE, Haas ME, MacLean MT, Witschey WR, Zhu X, Tcheandjieu C, Kember RL, Kranzler HR, Verma A, Giri A, Klarin DM, Sun YV, Huang J, Huffman JE, Creasy KT, Hand NJ, Liu CT, Long MT, Yao J, Budoff M, Tan J, Li X, Lin HJ, Chen YDI, Taylor KD, Chang RK, Krauss RM, Vilarinho S, Brancale J, Nielsen JB, Locke AE, Jones MB, Verweij N, Baras A, Reddy KR, Neuschwander-Tetri BA, Schwimmer JB, Sanyal AJ, Chalasani N, Ryan KA, Mitchell BD, Gill D, Wells AD, Manduchi E, Saiman Y, Mahmud N, Miller DR, Reaven PD, Phillips LS, Muralidhar S, DuVall SL, Lee JS, Assimes TL, Pyarajan S, Cho K, Edwards TL, Damrauer SM, Wilson PW, Gaziano JM, O'Donnell CJ, Khera AV, Grant SFA, Brown CD, Tsao PS, Saleheen D, Lotta LA, Bastarache L, Anstee QM, Daly AK, Meigs JB, Rotter JI, Lynch JA, Rader DJ, Voight BF, Chang KM. A multiancestry genome-wide association study of unexplained chronic ALT elevation as a proxy for nonalcoholic fatty liver disease with histological and radiological validation. Nat Genet 2022; 54:761-771. [PMID: 35654975 PMCID: PMC10024253 DOI: 10.1038/s41588-022-01078-z] [Citation(s) in RCA: 113] [Impact Index Per Article: 37.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/18/2020] [Accepted: 04/18/2022] [Indexed: 02/05/2023]
Abstract
Nonalcoholic fatty liver disease (NAFLD) is a growing cause of chronic liver disease. Using a proxy NAFLD definition of chronic elevation of alanine aminotransferase (cALT) levels without other liver diseases, we performed a multiancestry genome-wide association study (GWAS) in the Million Veteran Program (MVP) including 90,408 cALT cases and 128,187 controls. Seventy-seven loci exceeded genome-wide significance, including 25 without prior NAFLD or alanine aminotransferase associations, with one additional locus identified in European American-only and two in African American-only analyses (P < 5 × 10-8). External replication in histology-defined NAFLD cohorts (7,397 cases and 56,785 controls) or radiologic imaging cohorts (n = 44,289) replicated 17 single-nucleotide polymorphisms (SNPs) (P < 6.5 × 10-4), of which 9 were new (TRIB1, PPARG, MTTP, SERPINA1, FTO, IL1RN, COBLL1, APOH and IFI30). Pleiotropy analysis showed that 61 of 77 multiancestry and all 17 replicated SNPs were jointly associated with metabolic and/or inflammatory traits, revealing a complex model of genetic architecture. Our approach integrating cALT, histology and imaging reveals new insights into genetic liability to NAFLD.
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Affiliation(s)
- Marijana Vujkovic
- Corporal Michael J. Crescenz VA Medical Center, Philadelphia, PA, USA
- Department of Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA
| | - Shweta Ramdas
- Department of Genetics, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA
| | - Kim M Lorenz
- Corporal Michael J. Crescenz VA Medical Center, Philadelphia, PA, USA
- Department of Genetics, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA
- Department of Systems Pharmacology and Translational Therapeutics, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA
| | - Xiuqing Guo
- The Institute for Translational Genomics and Population Sciences, Department of Pediatrics, The Lundquist Institute for Biomedical Innovation at Harbor-UCLA Medical Center, Torrance, CA, USA
| | - Rebecca Darlay
- Population Health Sciences Institute, Newcastle University, Newcastle upon Tyne, UK
| | - Heather J Cordell
- Population Health Sciences Institute, Newcastle University, Newcastle upon Tyne, UK
| | - Jing He
- Department of Biomedical Informatics, Vanderbilt University Medical Center, Nashville, TN, USA
| | | | | | - Robert P Myers
- Gilead Sciences, Inc., Foster City, CA, USA
- The Liver Company, Palo Alto, CA, USA
| | - Carolin V Schneider
- Department of Genetics, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA
| | - Joseph Park
- Department of Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA
- Department of Genetics, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA
| | - Kyung Min Lee
- VA Salt Lake City Health Care System, Salt Lake City, UT, USA
| | - Marina Serper
- Corporal Michael J. Crescenz VA Medical Center, Philadelphia, PA, USA
- Department of Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA
| | - Rotonya M Carr
- Division of Gastroenterology, University of Washington, Seattle, WA, USA
| | - David E Kaplan
- Corporal Michael J. Crescenz VA Medical Center, Philadelphia, PA, USA
- Department of Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA
| | - Mary E Haas
- Broad Institute of MIT and Harvard, Cambridge, MA, USA
| | - Matthew T MacLean
- Department of Genetics, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA
| | - Walter R Witschey
- Department of Radiology, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA
| | - Xiang Zhu
- VA Palo Alto Health Care System, Palo Alto, CA, USA
- Department of Statistics, The Pennsylvania State University, University Park, PA, USA
- Huck Institutes of the Life Sciences, The Pennsylvania State University, University Park, PA, USA
- Department of Statistics, Stanford University, Stanford, CA, USA
| | - Catherine Tcheandjieu
- VA Palo Alto Health Care System, Palo Alto, CA, USA
- Department of Medicine, Stanford University School of Medicine, Stanford, CA, USA
| | - Rachel L Kember
- Mental Illness Research Education and Clinical Center, Corporal Michael J. Crescenz VA Medical Center, Philadelphia, PA, USA
- Department of Psychiatry, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA
| | - Henry R Kranzler
- Mental Illness Research Education and Clinical Center, Corporal Michael J. Crescenz VA Medical Center, Philadelphia, PA, USA
- Department of Psychiatry, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA
| | - Anurag Verma
- Corporal Michael J. Crescenz VA Medical Center, Philadelphia, PA, USA
- Department of Genetics, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA
| | - Ayush Giri
- Department of Obstetrics and Gynecology, Vanderbilt University Medical Center, Nashville, TN, USA
| | - Derek M Klarin
- VA Palo Alto Health Care System, Palo Alto, CA, USA
- Division of Vascular Surgery, Stanford University School of Medicine, Palo Alto, CA, USA
- Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA
| | - Yan V Sun
- Atlanta VA Medical Center, Decatur, GA, USA
- Department of Epidemiology, Emory University Rollins School of Public Health, Atlanta, GA, USA
| | - Jie Huang
- School of Public Health and Emergency Management, Southern University of Science and Technology, Shenzhen, Guangdong, China
| | | | - Kate Townsend Creasy
- Department of Genetics, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA
| | - Nicholas J Hand
- Department of Genetics, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA
| | - Ching-Ti Liu
- Department of Biostatistics, Boston University School of Public Health, Boston, MA, USA
| | - Michelle T Long
- Department of Medicine, Section of Gastroenterology, Boston University School of Medicine, Boston, MA, USA
| | - Jie Yao
- The Institute for Translational Genomics and Population Sciences, Department of Pediatrics, The Lundquist Institute for Biomedical Innovation at Harbor-UCLA Medical Center, Torrance, CA, USA
| | - Matthew Budoff
- Department of Cardiology, The Lundquist Institute for Biomedical Innovation at Harbor-UCLA Medical Center, Torrance, CA, USA
| | - Jingyi Tan
- The Institute for Translational Genomics and Population Sciences, Department of Pediatrics, The Lundquist Institute for Biomedical Innovation at Harbor-UCLA Medical Center, Torrance, CA, USA
| | - Xiaohui Li
- The Institute for Translational Genomics and Population Sciences, Department of Pediatrics, The Lundquist Institute for Biomedical Innovation at Harbor-UCLA Medical Center, Torrance, CA, USA
| | - Henry J Lin
- The Institute for Translational Genomics and Population Sciences, Department of Pediatrics, The Lundquist Institute for Biomedical Innovation at Harbor-UCLA Medical Center, Torrance, CA, USA
| | - Yii-Der Ida Chen
- The Institute for Translational Genomics and Population Sciences, Department of Pediatrics, The Lundquist Institute for Biomedical Innovation at Harbor-UCLA Medical Center, Torrance, CA, USA
| | - Kent D Taylor
- The Institute for Translational Genomics and Population Sciences, Department of Pediatrics, The Lundquist Institute for Biomedical Innovation at Harbor-UCLA Medical Center, Torrance, CA, USA
| | - Ruey-Kang Chang
- The Institute for Translational Genomics and Population Sciences, Department of Pediatrics, The Lundquist Institute for Biomedical Innovation at Harbor-UCLA Medical Center, Torrance, CA, USA
| | - Ronald M Krauss
- Departments of Pediatrics and Medicine, University of California, San Francisco, San Francisco, CA, USA
| | - Silvia Vilarinho
- Section of Digestive Diseases, Department of Internal Medicine, and Department of Pathology, Yale School of Medicine, New Haven, CT, USA
| | - Joseph Brancale
- Section of Digestive Diseases, Department of Internal Medicine, and Department of Pathology, Yale School of Medicine, New Haven, CT, USA
| | | | | | | | | | - Aris Baras
- Regeneron Genetics Center, Tarrytown, NY, USA
| | - K Rajender Reddy
- Department of Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA
| | | | - Jeffrey B Schwimmer
- Department of Pediatrics, University of California San Diego, La Jolla, CA, USA
| | - Arun J Sanyal
- Department of Internal Medicine, Virginia Commonwealth University School of Medicine, Richmond, VA, USA
| | - Naga Chalasani
- Department of Medicine, Indiana University School of Medicine, Indianapolis, IN, USA
| | - Kathleen A Ryan
- Program for Personalized and Genomic Medicine, Division of Endocrinology, Diabetes and Nutrition, Department of Medicine, University of Maryland School of Medicine, Baltimore, MD, USA
| | - Braxton D Mitchell
- Program for Personalized and Genomic Medicine, Division of Endocrinology, Diabetes and Nutrition, Department of Medicine, University of Maryland School of Medicine, Baltimore, MD, USA
| | - Dipender Gill
- Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London, London, UK
| | - Andrew D Wells
- Department of Pathology and Laboratory Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA
- Department of Pathology, Children's Hospital of Philadelphia, Philadelphia, PA, USA
| | - Elisabetta Manduchi
- Department of Genetics, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA
| | - Yedidya Saiman
- Department of Medicine, Section of Hepatology, Lewis Katz School of Medicine at Temple University, Temple University Hospital, Philadelphia, PA, USA
| | - Nadim Mahmud
- Department of Medicine, Division of Gastroenterology, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA
| | - Donald R Miller
- Center for Healthcare Organization and Implementation Research, Bedford VA Healthcare System, Bedford, MA, USA
- Center for Population Health, Department of Biomedical and Nutritional Sciences, University of Massachusetts, Lowell, MA, USA
| | - Peter D Reaven
- Phoenix VA Health Care System, Phoenix, AZ, USA
- College of Medicine, University of Arizona, Phoenix, AZ, USA
| | - Lawrence S Phillips
- Atlanta VA Medical Center, Decatur, GA, USA
- Division of Endocrinology, Emory University School of Medicine, Atlanta, GA, USA
| | - Sumitra Muralidhar
- Office of Research and Development, Veterans Health Administration, Washington, DC, USA
| | - Scott L DuVall
- VA Salt Lake City Health Care System, Salt Lake City, UT, USA
- Department of Medicine, University of Utah School of Medicine, Salt Lake City, UT, USA
| | - Jennifer S Lee
- VA Palo Alto Health Care System, Palo Alto, CA, USA
- Department of Medicine, Stanford University School of Medicine, Stanford, CA, USA
| | - Themistocles L Assimes
- VA Palo Alto Health Care System, Palo Alto, CA, USA
- Department of Medicine, Stanford University School of Medicine, Stanford, CA, USA
- Stanford Cardiovascular Institute, Stanford University School of Medicine, Stanford, CA, USA
| | - Saiju Pyarajan
- VA Boston Healthcare System, Boston, MA, USA
- Department of Medicine, Brigham Women's Hospital, Boston, MA, USA
- Department of Medicine, Harvard Medical School, Boston, MA, USA
| | - Kelly Cho
- VA Boston Healthcare System, Boston, MA, USA
- Department of Medicine, Brigham Women's Hospital, Boston, MA, USA
- Department of Medicine, Harvard Medical School, Boston, MA, USA
| | - Todd L Edwards
- Nashville VA Medical Center, Nashville, TN, USA
- Division of Epidemiology, Department of Medicine, Vanderbilt Genetics Institute, Vanderbilt University Medical Center, Nashville, TN, USA
| | - Scott M Damrauer
- Corporal Michael J. Crescenz VA Medical Center, Philadelphia, PA, USA
- Department of Genetics, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA
- Department of Surgery, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA
| | - Peter W Wilson
- Atlanta VA Medical Center, Decatur, GA, USA
- Division of Cardiology, Emory University School of Medicine, Atlanta, GA, USA
| | - J Michael Gaziano
- VA Boston Healthcare System, Boston, MA, USA
- Department of Medicine, Brigham Women's Hospital, Boston, MA, USA
| | - Christopher J O'Donnell
- VA Boston Healthcare System, Boston, MA, USA
- Department of Medicine, Brigham Women's Hospital, Boston, MA, USA
- Department of Medicine, Harvard Medical School, Boston, MA, USA
| | - Amit V Khera
- Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA
- Department of Medicine, Harvard Medical School, Boston, MA, USA
- Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA, USA
| | - Struan F A Grant
- Department of Genetics, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA
- Department of Pediatrics, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA
- Division of Human Genetics, Children's Hospital of Philadelphia, Philadelphia, PA, USA
| | - Christopher D Brown
- Department of Genetics, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA
| | - Philip S Tsao
- VA Palo Alto Health Care System, Palo Alto, CA, USA
- Department of Medicine, Stanford University School of Medicine, Stanford, CA, USA
- Stanford Cardiovascular Institute, Stanford University School of Medicine, Stanford, CA, USA
| | - Danish Saleheen
- Department of Medicine, Columbia University Irving Medical Center, New York, NY, USA
- Department of Cardiology, Columbia University Irving Medical Center, New York, NY, USA
- Center for Non-Communicable Diseases, Karachi, Sindh, Pakistan
| | | | - Lisa Bastarache
- Department of Biomedical Informatics, Vanderbilt University Medical Center, Nashville, TN, USA
| | - Quentin M Anstee
- Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, UK
- Newcastle NIHR Biomedical Research Centre, Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle upon Tyne, UK
| | - Ann K Daly
- Newcastle NIHR Biomedical Research Centre, Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle upon Tyne, UK
| | - James B Meigs
- Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA
- Department of Medicine, Harvard Medical School, Boston, MA, USA
- Division of General Internal Medicine, Massachusetts General Hospital, Boston, MA, USA
| | - Jerome I Rotter
- The Institute for Translational Genomics and Population Sciences, Department of Pediatrics, The Lundquist Institute for Biomedical Innovation at Harbor-UCLA Medical Center, Torrance, CA, USA
| | - Julie A Lynch
- VA Salt Lake City Health Care System, Salt Lake City, UT, USA
- Department of Medicine, University of Utah School of Medicine, Salt Lake City, UT, USA
- College of Nursing and Health Sciences, University of Massachusetts, Lowell, MA, USA
| | - Daniel J Rader
- Department of Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA
- Department of Genetics, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA
| | - Benjamin F Voight
- Corporal Michael J. Crescenz VA Medical Center, Philadelphia, PA, USA.
- Department of Genetics, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA.
- Department of Systems Pharmacology and Translational Therapeutics, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA.
- Institute of Translational Medicine and Therapeutics, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA.
| | - Kyong-Mi Chang
- Corporal Michael J. Crescenz VA Medical Center, Philadelphia, PA, USA.
- Department of Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA.
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Ndakotsu A, Vivekanandan G. The Role of Thiazolidinediones in the Amelioration of Nonalcoholic Fatty Liver Disease: A Systematic Review. Cureus 2022; 14:e25380. [PMID: 35765391 PMCID: PMC9233742 DOI: 10.7759/cureus.25380] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/27/2022] [Accepted: 05/27/2022] [Indexed: 11/05/2022] Open
Abstract
Non-alcoholic fatty liver disease (NAFLD) is a broad term encompassing hepatic steatosis and non-alcoholic steatohepatitis (NASH), a form of chronic hepatitis. This may, unfortunately, lead to terminal complications like cirrhosis and hepatocellular carcinoma (HCC). NAFLD is strongly associated with obesity, type 2 diabetes (T2DM), hypertension, and metabolic syndrome. The growing prevalence of NAFLD, its associated conditions, and its complications are alarming. The insulin sensitizer group "thiazolidinediones" has shown some therapeutic benefits in this condition. This systematic review is intended to focus on the clinical efficacy of this group in patients with NAFLD, employing PubMed, Google Scholar, and the Cochrane Library as databases. We discovered 10 randomized control trials (RCTs; nine involving pioglitazone and one involving rosiglitazone) involving 887 participants. All studies varied in duration from 6 to 24 months. Most of the involved trials had a small number of participants, and the intrinsic quality of the studies was mixed. Pioglitazone consistently improved histological parameters and normalized liver transaminases, although evidence supporting the benefits of other drugs in this class was minimal. Thiazolidinediones, particularly pioglitazone, have proven efficacious in patients with NAFLD/NASH. However, more extensive trials need to be carried out to investigate this drug class's benefits further. Unfortunately, this drug has attendant side effects like weight gain and fractures, limiting its widespread use; hence, careful selection for likely candidates is imperative.
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Affiliation(s)
- Andrew Ndakotsu
- Internal Medicine, California Institute of Behavioral Neurosciences and Psychology, Fairfield, USA
| | - Govinathan Vivekanandan
- Internal Medicine, California Institute of Behavioral Neurosciences and Psychology, Fairfield, USA
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Lange NF, Graf V, Caussy C, Dufour JF. PPAR-Targeted Therapies in the Treatment of Non-Alcoholic Fatty Liver Disease in Diabetic Patients. Int J Mol Sci 2022; 23:ijms23084305. [PMID: 35457120 PMCID: PMC9028563 DOI: 10.3390/ijms23084305] [Citation(s) in RCA: 43] [Impact Index Per Article: 14.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/21/2022] [Revised: 04/06/2022] [Accepted: 04/08/2022] [Indexed: 02/06/2023] Open
Abstract
Peroxisome proliferator-activated receptors (PPAR), ligand-activated transcription factors of the nuclear hormone receptor superfamily, have been identified as key metabolic regulators in the liver, skeletal muscle, and adipose tissue, among others. As a leading cause of liver disease worldwide, non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH) cause a significant burden worldwide and therapeutic strategies are needed. This review provides an overview of the evidence on PPAR-targeted treatment of NAFLD and NASH in individuals with type 2 diabetes mellitus. We considered current evidence from clinical trials and observational studies as well as the impact of treatment on comorbid metabolic conditions such as obesity, dyslipidemia, and cardiovascular disease. Future areas of research, such as possible sexually dimorphic effects of PPAR-targeted therapies, are briefly reviewed.
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Affiliation(s)
- Naomi F. Lange
- Department of Visceral Surgery and Medicine, Inselspital, Bern University Hospital, University of Bern, 3010 Bern, Switzerland
- Graduate School for Health Sciences, University of Bern, 3012 Bern, Switzerland
- Correspondence: (N.F.L.); (J.-F.D.)
| | - Vanessa Graf
- Department of Diabetes, Endocrinology, Clinical Nutrition, and Metabolism, Inselspital, Bern University Hospital, University of Bern, 3010 Bern, Switzerland;
| | - Cyrielle Caussy
- Univ Lyon, CarMen Laboratory, INSERM, INRA, INSA Lyon, Université Claude Bernard Lyon 1, 69495 Pierre-Bénite, France;
- Département Endocrinologie, Diabète et Nutrition, Hôpital Lyon Sud, Hospices Civils de Lyon, 69495 Pierre-Bénite, France
| | - Jean-François Dufour
- Centre des Maladies Digestives, 1003 Lausanne, Switzerland
- Swiss NASH Foundation, 3011 Bern, Switzerland
- Correspondence: (N.F.L.); (J.-F.D.)
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Sun SF, Zhong HJ, Zhao YL, Ma XY, Luo JB, Zhu L, Zhang YT, Wang WX, Luo XD, Geng JW. Indole alkaloids of Alstonia scholaris (L.) R. Br. alleviated nonalcoholic fatty liver disease in mice fed with high-fat diet. NATURAL PRODUCTS AND BIOPROSPECTING 2022; 12:14. [PMID: 35364708 PMCID: PMC8975985 DOI: 10.1007/s13659-022-00335-2] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 02/17/2022] [Accepted: 03/17/2022] [Indexed: 05/06/2023]
Abstract
Alstonia scholaris (L.) R. Br (Apocynaceae) is a well-documented medicinal plant for treating respiratory diseases, liver diseases and diabetes traditionally. The current study aimed to investigate the effects of TA on non-alcoholic fatty liver disease (NAFLD). A NAFLD model was established using mice fed a high-fat diet (HFD) and administered with TA (7.5, 15 and 30 mg/kg) orally for 6 weeks. The biochemical parameters, expressions of lipid metabolism-related genes or proteins were analyzed. Furthermore, histopathological examinations were evaluated with Hematoxylin-Eosin and MASSON staining. TA treatment significantly decreased the bodyweight of HFD mice. The concentrations of low-density lipoprotein (LDL), triglyceride (TG), aspartate aminotransferase (AST) and alanine aminotransferase (ALT) were also decreased significantly in TA-treated mice group, accompanied by an increase in high-density lipoprotein (HDL). Furthermore, TA alleviated hepatic steatosis injury and lipid droplet accumulation of liver tissues. The liver mRNA levels involved in hepatic lipid synthesis such as sterol regulatory element-binding protein 1C (SREBP-1C), regulators of liver X receptor α (LXRα), peroxisome proliferator activated receptor (PPAR)γ, acetyl-CoA carboxylase (ACC1) and stearyl coenzyme A dehydrogenase-1 (SCD1), were markedly decreased, while the expressions involved in the regulation of fatty acid oxidation, PPARα, carnitine palmitoyl transterase 1 (CPT1A), and acyl coenzyme A oxidase 1 (ACOX1) were increased in TA-treated mice. TA might attenuate NAFLD by regulating hepatic lipogenesis and fatty acid oxidation.
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Affiliation(s)
- Shui-Fen Sun
- Department of Infectious Disease and Hepatic Disease, First People's Hospital of Yunnan Province, Affiliated Hospital of Kunming University of Science and Technology, Kunming, 650032, Yunnan, China
- School of Medicine, Kunming University of Science and Technology, Kunming, 650500, Yunnan, China
| | - Hui-Jie Zhong
- Department of Infectious Disease and Hepatic Disease, First People's Hospital of Yunnan Province, Affiliated Hospital of Kunming University of Science and Technology, Kunming, 650032, Yunnan, China
- School of Medicine, Kunming University of Science and Technology, Kunming, 650500, Yunnan, China
- Faculty of Life Science and Technology, Kunming University of Science and Technology, Kunming, 650500, Yunnan, China
| | - Yun-Li Zhao
- State Key Laboratory of Phytochemistry and Plant Resources in West China, Kunming Institute of Botany, Chinese Academy of Sciences, Kunming, 650201, People's Republic of China
| | - Xiu-Ying Ma
- Department of Infectious Disease and Hepatic Disease, First People's Hospital of Yunnan Province, Affiliated Hospital of Kunming University of Science and Technology, Kunming, 650032, Yunnan, China
| | - Jin-Bo Luo
- Department of Infectious Disease and Hepatic Disease, First People's Hospital of Yunnan Province, Affiliated Hospital of Kunming University of Science and Technology, Kunming, 650032, Yunnan, China
| | - Ling Zhu
- Department of Infectious Disease and Hepatic Disease, First People's Hospital of Yunnan Province, Affiliated Hospital of Kunming University of Science and Technology, Kunming, 650032, Yunnan, China
| | - Yu-Ting Zhang
- Department of Infectious Disease and Hepatic Disease, First People's Hospital of Yunnan Province, Affiliated Hospital of Kunming University of Science and Technology, Kunming, 650032, Yunnan, China
| | - Wen-Xue Wang
- Department of Infectious Disease and Hepatic Disease, First People's Hospital of Yunnan Province, Affiliated Hospital of Kunming University of Science and Technology, Kunming, 650032, Yunnan, China.
- School of Medicine, Kunming University of Science and Technology, Kunming, 650500, Yunnan, China.
| | - Xiao-Dong Luo
- State Key Laboratory of Phytochemistry and Plant Resources in West China, Kunming Institute of Botany, Chinese Academy of Sciences, Kunming, 650201, People's Republic of China.
| | - Jia-Wei Geng
- Department of Infectious Disease and Hepatic Disease, First People's Hospital of Yunnan Province, Affiliated Hospital of Kunming University of Science and Technology, Kunming, 650032, Yunnan, China.
- School of Medicine, Kunming University of Science and Technology, Kunming, 650500, Yunnan, China.
- Faculty of Life Science and Technology, Kunming University of Science and Technology, Kunming, 650500, Yunnan, China.
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Chen YW, Diamante G, Ding J, Nghiem TX, Yang J, Ha SM, Cohn P, Arneson D, Blencowe M, Garcia J, Zaghari N, Patel P, Yang X. PharmOmics: A species- and tissue-specific drug signature database and gene-network-based drug repositioning tool. iScience 2022; 25:104052. [PMID: 35345455 PMCID: PMC8957031 DOI: 10.1016/j.isci.2022.104052] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/18/2021] [Revised: 01/29/2022] [Accepted: 03/08/2022] [Indexed: 12/29/2022] Open
Abstract
Drug development has been hampered by a high failure rate in clinical trials due to our incomplete understanding of drug functions across organs and species. Therefore, elucidating species- and tissue-specific drug functions can provide insights into therapeutic efficacy, potential adverse effects, and interspecies differences necessary for effective translational medicine. Here, we present PharmOmics, a drug knowledgebase and analytical tool that is hosted on an interactive web server. Using tissue- and species-specific transcriptome data from human, mouse, and rat curated from different databases, we implemented a gene-network-based approach for drug repositioning. We demonstrate the potential of PharmOmics to retrieve known therapeutic drugs and identify drugs with tissue toxicity using in silico performance assessment. We further validated predicted drugs for nonalcoholic fatty liver disease in mice. By combining tissue- and species-specific in vivo drug signatures with gene networks, PharmOmics serves as a complementary tool to support drug characterization and network-based medicine.
Development of PharmOmics, a platform for drug repositioning and toxicity prediction Contains >18000 species/tissue-specific gene signatures for 941 drugs and chemicals Benchmarked and validated network-based drug repositioning and toxicity prediction PharmOmics is freely accessible via an online web server to facilitate user access
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Affiliation(s)
- Yen-Wei Chen
- Department of Integrative Biology and Physiology, University of California, Los Angeles, Los Angeles, CA 90095, USA
- Interdepartmental Program of Molecular Toxicology, University of California, Los Angeles, Los Angeles, CA 90095, USA
| | - Graciel Diamante
- Department of Integrative Biology and Physiology, University of California, Los Angeles, Los Angeles, CA 90095, USA
- Interdepartmental Program of Molecular Toxicology, University of California, Los Angeles, Los Angeles, CA 90095, USA
| | - Jessica Ding
- Department of Integrative Biology and Physiology, University of California, Los Angeles, Los Angeles, CA 90095, USA
- Interdepartmental Program of Molecular, Cellular, & Integrative Physiology, Los Angeles, Los Angeles, CA 90095, USA
| | - Thien Xuan Nghiem
- Department of Integrative Biology and Physiology, University of California, Los Angeles, Los Angeles, CA 90095, USA
| | - Jessica Yang
- Department of Integrative Biology and Physiology, University of California, Los Angeles, Los Angeles, CA 90095, USA
| | - Sung-Min Ha
- Department of Integrative Biology and Physiology, University of California, Los Angeles, Los Angeles, CA 90095, USA
| | - Peter Cohn
- Department of Integrative Biology and Physiology, University of California, Los Angeles, Los Angeles, CA 90095, USA
| | - Douglas Arneson
- Department of Integrative Biology and Physiology, University of California, Los Angeles, Los Angeles, CA 90095, USA
- Interdepartmental Program of Bioinformatics, University of California, Los Angeles, Los Angeles, CA 90095, USA
| | - Montgomery Blencowe
- Department of Integrative Biology and Physiology, University of California, Los Angeles, Los Angeles, CA 90095, USA
- Interdepartmental Program of Molecular, Cellular, & Integrative Physiology, Los Angeles, Los Angeles, CA 90095, USA
| | - Jennifer Garcia
- Department of Integrative Biology and Physiology, University of California, Los Angeles, Los Angeles, CA 90095, USA
| | - Nima Zaghari
- Department of Integrative Biology and Physiology, University of California, Los Angeles, Los Angeles, CA 90095, USA
| | - Paul Patel
- Department of Integrative Biology and Physiology, University of California, Los Angeles, Los Angeles, CA 90095, USA
| | - Xia Yang
- Department of Integrative Biology and Physiology, University of California, Los Angeles, Los Angeles, CA 90095, USA
- Interdepartmental Program of Molecular Toxicology, University of California, Los Angeles, Los Angeles, CA 90095, USA
- Interdepartmental Program of Molecular, Cellular, & Integrative Physiology, Los Angeles, Los Angeles, CA 90095, USA
- Interdepartmental Program of Bioinformatics, University of California, Los Angeles, Los Angeles, CA 90095, USA
- Institute for Quantitative and Computational Biosciences, University of California, Los Angeles, Los Angeles, CA 90095, USA
- Corresponding author
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The Coexistence of Nonalcoholic Fatty Liver Disease and Type 2 Diabetes Mellitus. J Clin Med 2022; 11:jcm11051375. [PMID: 35268466 PMCID: PMC8910939 DOI: 10.3390/jcm11051375] [Citation(s) in RCA: 22] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/24/2022] [Revised: 02/28/2022] [Accepted: 03/01/2022] [Indexed: 12/12/2022] Open
Abstract
The incidence of nonalcoholic fatty liver disease (NAFLD) is growing worldwide. Epidemiological data suggest a strong relationship between NAFLD and T2DM. This is associated with common risk factors and pathogenesis, where obesity, insulin resistance and dyslipidemia play pivotal roles. Expanding knowledge on the coexistence of NAFLD and T2DM could not only protect against liver damage and glucotoxicity, but may also theoretically prevent the subsequent occurrence of other diseases, such as cancer and cardiovascular disorders, as well as influence morbidity and mortality rates. In everyday clinical practice, underestimation of this problem is still observed. NAFLD is not looked for in T2DM patients; on the contrary, diagnosis for glucose metabolism disturbances is usually not performed in patients with NAFLD. However, simple and cost-effective methods of detection of fatty liver in T2DM patients are still needed, especially in outpatient settings. The treatment of NAFLD, especially where it coexists with T2DM, consists mainly of lifestyle modification. It is also suggested that some drugs, including hypoglycemic agents, may be used to treat NAFLD. Therefore, the aim of this review is to detail current knowledge of NAFLD and T2DM comorbidity, its prevalence, common pathogenesis, diagnostic procedures, complications and treatment, with special attention to outpatient clinics.
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Xenobiotic-Induced Aggravation of Metabolic-Associated Fatty Liver Disease. Int J Mol Sci 2022; 23:ijms23031062. [PMID: 35162986 PMCID: PMC8834714 DOI: 10.3390/ijms23031062] [Citation(s) in RCA: 22] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/14/2021] [Revised: 01/11/2022] [Accepted: 01/15/2022] [Indexed: 01/09/2023] Open
Abstract
Metabolic-associated fatty liver disease (MAFLD), which is often linked to obesity, encompasses a large spectrum of hepatic lesions, including simple fatty liver, steatohepatitis, cirrhosis and hepatocellular carcinoma. Besides nutritional and genetic factors, different xenobiotics such as pharmaceuticals and environmental toxicants are suspected to aggravate MAFLD in obese individuals. More specifically, pre-existing fatty liver or steatohepatitis may worsen, or fatty liver may progress faster to steatohepatitis in treated patients, or exposed individuals. The mechanisms whereby xenobiotics can aggravate MAFLD are still poorly understood and are currently under deep investigations. Nevertheless, previous studies pointed to the role of different metabolic pathways and cellular events such as activation of de novo lipogenesis and mitochondrial dysfunction, mostly associated with reactive oxygen species overproduction. This review presents the available data gathered with some prototypic compounds with a focus on corticosteroids and rosiglitazone for pharmaceuticals as well as bisphenol A and perfluorooctanoic acid for endocrine disruptors. Although not typically considered as a xenobiotic, ethanol is also discussed because its abuse has dire consequences on obese liver.
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Negi CK, Babica P, Bajard L, Bienertova-Vasku J, Tarantino G. Insights into the molecular targets and emerging pharmacotherapeutic interventions for nonalcoholic fatty liver disease. Metabolism 2022; 126:154925. [PMID: 34740573 DOI: 10.1016/j.metabol.2021.154925] [Citation(s) in RCA: 148] [Impact Index Per Article: 49.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/12/2021] [Revised: 10/27/2021] [Accepted: 10/28/2021] [Indexed: 12/14/2022]
Abstract
Nonalcoholic fatty liver disease (NAFLD) is the most common form of chronic liver disease worldwide. With no Food and Drug Administration approved drugs, current treatment options include dietary restrictions and lifestyle modification. NAFLD is closely associated with metabolic disorders such as obesity, type 2 diabetes, and dyslipidemia. Hence, clinically various pharmacological approaches using existing drugs such as antidiabetic, anti-obesity, antioxidants, and cytoprotective agents have been considered in the management of NAFLD and nonalcoholic steatohepatitis (NASH). However, several pharmacological therapies aiming to alleviate NAFLD-NASH are currently being examined at various phases of clinical trials. Emerging data from these studies with drugs targeting diverse molecular mechanisms show promising outcomes. This review summarizes the current understanding of the pathogenic mechanisms of NAFLD and provides an insight into the pharmacological targets and emerging therapeutics with specific interventional mechanisms. In addition, we also discuss the importance and utility of new approach methodologies and regulatory perspectives for NAFLD-NASH drug development.
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Affiliation(s)
- Chander K Negi
- RECETOX, Faculty of Science, Masaryk University, Kotlarska 2, Brno, Czech Republic
| | - Pavel Babica
- RECETOX, Faculty of Science, Masaryk University, Kotlarska 2, Brno, Czech Republic.
| | - Lola Bajard
- RECETOX, Faculty of Science, Masaryk University, Kotlarska 2, Brno, Czech Republic
| | - Julie Bienertova-Vasku
- RECETOX, Faculty of Science, Masaryk University, Kotlarska 2, Brno, Czech Republic; Department of Pathological Physiology, Faculty of Medicine, Masaryk University, Brno, Czech Republic
| | - Giovanni Tarantino
- Department of Clinical Medicine and Surgery, Federico II University Medical School of Naples, Naples, Italy
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Santos-Laso A, Gutiérrez-Larrañaga M, Alonso-Peña M, Medina JM, Iruzubieta P, Arias-Loste MT, López-Hoyos M, Crespo J. Pathophysiological Mechanisms in Non-Alcoholic Fatty Liver Disease: From Drivers to Targets. Biomedicines 2021; 10:biomedicines10010046. [PMID: 35052726 PMCID: PMC8773141 DOI: 10.3390/biomedicines10010046] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2021] [Revised: 12/23/2021] [Accepted: 12/23/2021] [Indexed: 02/07/2023] Open
Abstract
Non-alcoholic fatty liver disease (NAFLD) is characterized by the excessive and detrimental accumulation of liver fat as a result of high-caloric intake and/or cellular and molecular abnormalities. The prevalence of this pathological event is increasing worldwide, and is intimately associated with obesity and type 2 diabetes mellitus, among other comorbidities. To date, only therapeutic strategies based on lifestyle changes have exhibited a beneficial impact on patients with NAFLD, but unfortunately this approach is often difficult to implement, and shows poor long-term adherence. For this reason, great efforts are being made to elucidate and integrate the underlying pathological molecular mechanism, and to identify novel and promising druggable targets for therapy. In this regard, a large number of clinical trials testing different potential compounds have been performed, albeit with no conclusive results yet. Importantly, many other clinical trials are currently underway with results expected in the near future. Here, we summarize the key aspects of NAFLD pathogenesis and therapeutic targets in this frequent disorder, highlighting the most recent advances in the field and future research directions.
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Affiliation(s)
- Alvaro Santos-Laso
- Department of Gastroenterology and Hepatology, Marqués de Valdecilla University Hospital, Valdecilla Biomedical Research Institute (IDIVAL), 39008 Santander, Spain; (M.A.-P.); (J.M.M.); (P.I.); (M.T.A.-L.)
- Correspondence: (A.S.-L.); (J.C.)
| | - María Gutiérrez-Larrañaga
- Department of Immunology, Marqués de Valdecilla University Hospital, Valdecilla Biomedical Research Institute (IDIVAL), 39008 Santander, Spain; (M.G.-L.); (M.L.-H.)
| | - Marta Alonso-Peña
- Department of Gastroenterology and Hepatology, Marqués de Valdecilla University Hospital, Valdecilla Biomedical Research Institute (IDIVAL), 39008 Santander, Spain; (M.A.-P.); (J.M.M.); (P.I.); (M.T.A.-L.)
| | - Juan M. Medina
- Department of Gastroenterology and Hepatology, Marqués de Valdecilla University Hospital, Valdecilla Biomedical Research Institute (IDIVAL), 39008 Santander, Spain; (M.A.-P.); (J.M.M.); (P.I.); (M.T.A.-L.)
| | - Paula Iruzubieta
- Department of Gastroenterology and Hepatology, Marqués de Valdecilla University Hospital, Valdecilla Biomedical Research Institute (IDIVAL), 39008 Santander, Spain; (M.A.-P.); (J.M.M.); (P.I.); (M.T.A.-L.)
- National Institute for the Study of Liver and Gastrointestinal Diseases (CIBERehd, Instituto de Salud Carlos III), 28029 Madrid, Spain
| | - María Teresa Arias-Loste
- Department of Gastroenterology and Hepatology, Marqués de Valdecilla University Hospital, Valdecilla Biomedical Research Institute (IDIVAL), 39008 Santander, Spain; (M.A.-P.); (J.M.M.); (P.I.); (M.T.A.-L.)
- National Institute for the Study of Liver and Gastrointestinal Diseases (CIBERehd, Instituto de Salud Carlos III), 28029 Madrid, Spain
| | - Marcos López-Hoyos
- Department of Immunology, Marqués de Valdecilla University Hospital, Valdecilla Biomedical Research Institute (IDIVAL), 39008 Santander, Spain; (M.G.-L.); (M.L.-H.)
| | - Javier Crespo
- Department of Gastroenterology and Hepatology, Marqués de Valdecilla University Hospital, Valdecilla Biomedical Research Institute (IDIVAL), 39008 Santander, Spain; (M.A.-P.); (J.M.M.); (P.I.); (M.T.A.-L.)
- National Institute for the Study of Liver and Gastrointestinal Diseases (CIBERehd, Instituto de Salud Carlos III), 28029 Madrid, Spain
- Correspondence: (A.S.-L.); (J.C.)
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The Role and Mechanism of Oxidative Stress and Nuclear Receptors in the Development of NAFLD. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2021; 2021:6889533. [PMID: 34745420 PMCID: PMC8566046 DOI: 10.1155/2021/6889533] [Citation(s) in RCA: 53] [Impact Index Per Article: 13.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 04/11/2021] [Accepted: 10/11/2021] [Indexed: 12/12/2022]
Abstract
The overproduction of reactive oxygen species (ROS) and consequent oxidative stress contribute to the pathogenesis of acute and chronic liver diseases. It is now acknowledged that nonalcoholic fatty liver disease (NAFLD) is characterized as a redox-centered disease due to the role of ROS in hepatic metabolism. However, the underlying mechanisms accounting for these alternations are not completely understood. Several nuclear receptors (NRs) are dysregulated in NAFLD, and have a direct influence on the expression of a set of genes relating to the progress of hepatic lipid homeostasis and ROS generation. Meanwhile, the NRs act as redox sensors in response to metabolic stress. Therefore, targeting NRs may represent a promising strategy for improving oxidation damage and treating NAFLD. This review summarizes the link between impaired lipid metabolism and oxidative stress and highlights some NRs involved in regulating oxidant/antioxidant turnover in the context of NAFLD, shedding light on potential therapies based on NR-mediated modulation of ROS generation and lipid accumulation.
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Lee SM, Muratalla J, Diaz-Ruiz A, Remon-Ruiz P, McCann M, Liew CW, Kineman RD, Cordoba-Chacon J. Rosiglitazone Requires Hepatocyte PPARγ Expression to Promote Steatosis in Male Mice With Diet-Induced Obesity. Endocrinology 2021; 162:6356057. [PMID: 34417811 PMCID: PMC8428295 DOI: 10.1210/endocr/bqab175] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/20/2021] [Indexed: 12/12/2022]
Abstract
Thiazolidinediones (TZD) are peroxisome proliferator-activated receptor γ (PPARγ) agonists that may reduce hepatic steatosis through their effects in adipose tissue and therefore have been assessed as potential therapies to treat nonalcoholic fatty liver disease (NAFLD) in humans. However, some studies suggest that expression and activation of hepatocyte PPARγ promotes steatosis and that would limit the benefits of TZD as a NAFLD therapy. To further explore this possibility, we examined the impact of short-term rosiglitazone maleate treatment after the development of moderate or severe diet-induced obesity, in both control and adult-onset hepatocyte-specific PPARγ knockout (PpargΔHep) mice. Independent of the level of obesity and hepatic PPARγ expression, the TZD treatment enhanced insulin sensitivity, associated with an increase in white adipose tissue (WAT) fat accumulation, consistent with clinical observations. However, TZD treatment increased hepatic triglyceride content only in control mice with severe obesity. Under these conditions, PpargΔHep reduced diet-induced steatosis and prevented the steatogenic effects of short-term TZD treatment. In these mice, subcutaneous WAT was enlarged and associated with increased levels of adiponectin, while hepatic levels of phosphorylated adenosine 5'-monophosphate-activated protein kinase were also increased. In addition, in mice with severe obesity, the expression of hepatic Cd36, Cidea, Cidec, Fabp4, Fasn, and Scd-1 was increased by TZD in a PPARγ-dependent manner. Taken together, these results demonstrate that hepatocyte PPARγ expression offsets the antisteatogenic actions of TZD in mice with severe obesity. Therefore, in obese and insulin resistant humans, TZD-mediated activation of hepatocyte PPARγ may limit the therapeutic potential of TZD to treat NAFLD.
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Affiliation(s)
- Samuel M Lee
- Department of Medicine, Division of Endocrinology, Diabetes and Metabolism, University of Illinois at Chicago, Chicago, IL, USA
| | - Jose Muratalla
- Department of Medicine, Division of Endocrinology, Diabetes and Metabolism, University of Illinois at Chicago, Chicago, IL, USA
| | | | - Pablo Remon-Ruiz
- Endocrinology and Clinical Nutrition Department, Virgen del Rocío University Hospital, Institute of Biomedicine of Seville (IBIS), Seville, Spain
| | - Maximilian McCann
- Department of Physiology and Biophysics, University of Illinois at Chicago, Chicago, IL, USA
| | - Chong W Liew
- Department of Physiology and Biophysics, University of Illinois at Chicago, Chicago, IL, USA
| | - Rhonda D Kineman
- Department of Medicine, Division of Endocrinology, Diabetes and Metabolism, University of Illinois at Chicago, Chicago, IL, USA
- Research and Development Division. Jesse Brown VA Medical Center, Chicago, IL, USA
| | - Jose Cordoba-Chacon
- Department of Medicine, Division of Endocrinology, Diabetes and Metabolism, University of Illinois at Chicago, Chicago, IL, USA
- Correspondence: Jose Cordoba-Chacon, PhD, Department of Medicine, Section of Endocrinology, Diabetes and Metabolism. 835 S. Wolcott Ave (North Entrance) Suite E625. M/C 640. Chicago, IL, USA.
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Satiya J, Snyder HS, Singh SP, Satapathy SK. Narrative review of current and emerging pharmacological therapies for nonalcoholic steatohepatitis. Transl Gastroenterol Hepatol 2021; 6:60. [PMID: 34805582 PMCID: PMC8573363 DOI: 10.21037/tgh-20-247] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/14/2020] [Accepted: 09/25/2020] [Indexed: 12/28/2022] Open
Abstract
Nonalcoholic steatohepatitis (NASH) is the most common cause of chronic liver disease today, and it has now emerged as the leading etiology of end-stage liver disease requiring liver transplantation. It is a progressive form of non-alcoholic fatty liver disease which can not only progress to cirrhosis of liver and hepatocellular carcinoma (HCC), but is associated with increased cardiovascular risks too. Despite all the advances in the understanding of the risk factors and the pathogenetic pathways involved in the pathogenesis and progression of NASH, an effective therapy for NASH has not been developed yet. Although lifestyle modifications including dietary modifications and physical activity remain the mainstay of therapy, there is an unmet need to develop a drug or a combination of drugs which can not only reduce the fatty infiltration of the liver, but also arrest the development and progression of fibrosis and advancement to cirrhosis of liver and HCC. The pharmacologic therapies which are being developed target the various components believed to be involved in the pathogenesis of nonalcoholic fatty liver disease (NAFLD)/NASH which includes insulin resistance, lipid metabolism oxidative stress, lipid peroxidation, inflammatory and cell death pathways, and fibrosis. In this review, we summarize the current state of knowledge on pharmacotherapy of NASH, and also highlight the recent developments in the field, for optimizing the management and treatment of NASH.
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Affiliation(s)
- Jinendra Satiya
- Division of Gastroenterology and Hepatology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA
| | | | - Shivaram Prasad Singh
- Department of Gastroenterology, S.C.B. Medical College, Cuttack, India
- Kalinga Gastroenterology Foundation, Beam Diagnostics Centre, Cuttack, India
| | - Sanjaya K. Satapathy
- Division of Hepatology, Sandra Atlas Bass Center for Liver Diseases and Transplantation, Northwell Health, Manhasset, NY, USA
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