Nonalcoholic steatohepatitis: the role of peroxisome proliferator-activated receptors

Abstract

The increasing epidemic of obesity worldwide is linked to serious health effects, including increased prevalence of type 2 diabetes mellitus, cardiovascular disease and nonalcoholic fatty liver disease (NAFLD). NAFLD is the liver manifestation of the metabolic syndrome and includes the spectrum of liver steatosis (known as nonalcoholic fatty liver) and steatohepatitis (known as nonalcoholic steatohepatitis), which can evolve into progressive liver fibrosis and eventually cause cirrhosis. Although NAFLD is becoming the number one cause of chronic liver diseases, it is part of a systemic disease that affects many other parts of the body, including adipose tissue, pancreatic β-cells and the cardiovascular system. The pathomechanism of NAFLD is multifactorial across a spectrum of metabolic derangements and changes in the host microbiome that trigger low-grade inflammation in the liver and other organs. Peroxisome proliferator-activated receptors (PPARs) are a group of nuclear regulatory factors that provide fine tuning for key elements of glucose and fat metabolism and regulate inflammatory cell activation and fibrotic processes. This Review summarizes and discusses the current literature on NAFLD as the liver manifestation of the systemic metabolic syndrome and focuses on the role of PPARs in the pathomechanisms as well as in the potential targeting of disease.

Key points

  • Nonalcoholic steatohepatitis (NASH) is the fastest growing liver disease worldwide; however, it is often not recognized until advanced disease stages.

  • The management and treatment of NASH, the liver manifestation of the metabolic syndrome, require a holistic approach.

  • Peroxisome proliferator-activated receptors (PPARs) regulate metabolism, inflammation and fibrosis, all of which determine NASH progression.

  • There is an urgent need for medical therapy for patients with NASH.

  • Both PPARα-β/δ dual agonism as well as PPARγ agonism have shown beneficial effects on liver histology in phase IIb clinical trials for NASH.

  • Single, dual and pan-PPAR agonists are under development for the pharmacological treatment of NASH.

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Fig. 1: Relationships between NAFLD, T2DM and metabolic syndrome, CVD and HCC.
Fig. 2: The role of PPARs in NASH and fibrosis development.
Fig. 3: PPARs and inflammation.

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G.S. and S.F. researched data for the article, made a substantial contribution to discussion of content, wrote the article, and reviewed/edited the manuscript before submission. M.F.A., C.D.B., K.C., J.-F.D., M.R., F.S. and F.T. made a substantial contribution to the discussion of content and reviewed/edited the manuscript before submission.

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Correspondence to Sven Francque or Gyongyi Szabo.

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Competing interests

S.F. has a senior clinical research mandate from the Fund for Scientific Research (FWO) Flanders (1802154N) and has acted as advisor and/or lecturer for Roche, Gilead, Abbvie, Bayer, BMS, MSD, Janssen, Actelion, Astellas, Genfit, Inventiva, Intercept, Genentech and Galmed. G.S. has received research support from NIAAA (NIH), Gilead, Intercept, Allergan, Genfit, Novartis, SignaBlock, Shire, the University of Florida, BMS, Genentech, Takeda, and Vertex. She is a consultant/advisory board member for Allergan, Arrow Diagnostics, Pandion Therapeutics, Glympse Bio, Quest Diagnostic, Surrozen, Innovate Biopharmaceuticals, Alnylam, Zomagen, Novartis, Durect, Generon and Terrafirma. She is an author for UptoDate, editor for the American Association for the Study of Liver Diseases and Editor-in-Chief of Hepatology Communications. M.F.A. is supported by the National Institute of Health (NIH)/NIDDK Nonalcoholic Steatohepatitis Clinical Research Network (NASH CRN, U01DK061713, PI: A.M. Diehl) and is an advisor/consultant for Bristol Myers Squibb, NGM Pharma, Inventiva, Taiwan J, Immuron, Prometheus, and Novo-Nordisk. Her institution receives funding for research from NIH/NIDDK, Inventiva, Enyo, Enanta, Allergan, Novartis, Genfit, Intercept, BMS, NGM Parma, Gilead, Conatus, Durect, Poxel, Madrigal, Celgene, Galactin, Galmed, Novo-Nordisk, Taiwan J, Prometheus, TARGET NASH, and Progenity. She serves on speaker’s bureau for Simply Speaking NASH, iHEP NASH, PRIME NASH Programming, Clinical Care Options, and Alexion. C.D.B. is supported by the National Institute for Health Research (NIHR) through the NIHR Southampton Biomedical Research Centre. He is a consultant for Inventiva. K.C. has received research support for the University of Florida as principal investigator from the NIH, Cirius, Echosens, Inventiva, Novartis, Novo Nordisk, Poxel, TARGET NASH and Zydus. He is a consultant for Allergan, Astra-Zeneca, BMS, Boehringer Ingelheim, Coherus, Eli Lilly, Genentech, Gilead, Janssen, Merck, Pfizer, Poxel, Prosciento, Novo Nordisk, Sanofi-Aventis, and TARGET NASH. J.-F.D. is a consultant/advisory board member for Abbvie, Allergan, Bayer, Bristol-Myers Squibb, Falk, Genfit, Genkyotex, Gilead Science, HepaRegenix, Intercept Pharma, Lilly, Merck, and Novartis. He serves as an investigator of studies supported by Abbvie, Bayer, BMS, Falk, Genfit, Gilead Science, Intercept, Inventiva, Lilly, Merck, and Novartis. M.R. has received research support from the Ministry of Culture and Science of the State of North Rhine-Westphalia and the German Federal Ministry of Health, grants from the European Fonds for Regional Development (EFRE-0400191), German Research Foundation (DFG, SFB 1116/2) and the Schmutzler Stiftung, serves as investigator of studies supported by Boehringer-Ingelheim Pharma, Nutricia/Danone, and Sanofi, and was advisor/consultant for Bristol-Myers Squibb, Eli Lilly, Gilead, Intercept Pharma, Novo Nordisk, Novartis, Poxel, Prosciento, Sanofi, Servier, and TARGET NASH. F.S. is a consultant to Pfizer, AstraZeneca, and Abbvie. F.T. has received research funding at Charité University Medicine Berlin from Allergan, Bristol-Myers Squibb, Galapagos, and Inventiva. He is a consultant for Allergan, Bayer, Boehringer Ingelheim, Galapagos, Galmed, Intercept, Inventiva, and Pfizer.

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Francque, S., Szabo, G., Abdelmalek, M.F. et al. Nonalcoholic steatohepatitis: the role of peroxisome proliferator-activated receptors. Nat Rev Gastroenterol Hepatol (2020). https://doi.org/10.1038/s41575-020-00366-5

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