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Review
. 2021 May 13;184(10):2537-2564.
doi: 10.1016/j.cell.2021.04.015.

Mechanisms and disease consequences of nonalcoholic fatty liver disease

Rohit Loomba  1 , Scott L Friedman  2 , Gerald I Shulman  3
Affiliations
Free article
Review

Mechanisms and disease consequences of nonalcoholic fatty liver disease

Rohit Loomba et al. Cell. .
Free article

Abstract

Nonalcoholic fatty liver disease (NAFLD) is the leading chronic liver disease worldwide. Its more advanced subtype, nonalcoholic steatohepatitis (NASH), connotes progressive liver injury that can lead to cirrhosis and hepatocellular carcinoma. Here we provide an in-depth discussion of the underlying pathogenetic mechanisms that lead to progressive liver injury, including the metabolic origins of NAFLD, the effect of NAFLD on hepatic glucose and lipid metabolism, bile acid toxicity, macrophage dysfunction, and hepatic stellate cell activation, and consider the role of genetic, epigenetic, and environmental factors that promote fibrosis progression and risk of hepatocellular carcinoma in NASH.

Keywords: fibrosis; insulin resistance; lipotoxicity; liver cancer; metabolism-associated fatty liver disease; nonalcoholic steatohepatitis.

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Conflict of interest statement

Declaration of interests R.L. serves as a consultant for Anylam/Regeneron, Amgen, Arrowhead Pharmaceuticals, AstraZeneca, Bristol Myers Squibb, CohBar, Eli Lilly, Galmed, Gilead, Glympse bio, Inipharm, Intercept, Ionis, Janssen, Madrigal, Metacrine, NGM Biopharmaceuticals, Novartis, Novo Nordisk, Pfizer, Sagimet, 89 bio, and Viking Therapeutics. In addition, his institution has received grant support from Allergan, Astrazeneca, Boehringer-Ingelheim, Bristol Myers Squibb, Eli Lilly, Galectin Therapeutics, Galmed Pharmaceuticals, Genfit, Gilead, Intercept, Inventiva, Janssen, Madrigal Pharmaceuticals, Merck, NGM Biopharmaceuticals, Pfizer, and Siemens. He is also co-founder of Liponexus; S.L.F. is a consultant to 89 Bio, Amgen, Axcella Health, Blade Therapeutics, Bristol Myers Squibb, Can-Fite Biopharma, Casma Therapeutics, ChemomAb, Escient Pharmaceuticals, Forbion, Galmed, Gordian Biotechnology, Glycotest, Glympse Bio, In sitro, Morphic Therapeutics, North Sea Therapeutics, Novartis, Ono Pharmaceuticals, Pfizer Pharmaceuticals, Scholar Rock, and Surrozen and has stock options (all less than 1% of company value) in Blade Therapeutics, Escient, Galectin, Galmed, Genfit, Glympse, Hepgene, Lifemax, Metacrine, Morphic Therapeutics, Nimbus, North Sea Therapeutics, Scholar Rock, and Surrozen. G.I.S. serves on the scientific advisory boards for Merck, Novo Nordisk, AstraZeneca, Gilead Sciences, Esperion, Generian, Levels, 89bio, and Janseen Research and Development. G.I.S. receives investigator-initiated support from AstraZeneca, Gilead Sciences, and Merck. G.I.S. is an inventor on Yale patents for liver-targeted mitochondrial uncoupling agents and controlled-release mitochondrial uncoupling agents for the treatment of NAFLD, NASH, T2D, and related metabolic disorders and is a scientific-cofounder of TLC.

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