Cited by 745Liver Disease Diagnosis and TreatmentDiet, Metabolism, and DiseaseDiabetes, Cardiovascular Risks, and Lipoproteins

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Nonalcoholic Fatty Liver Disease as a Nexus of Metabolic and Hepatic Diseases

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Samuel, Varman T., Shulman, Gerald I.·2018·Cell Metabolism

DOI 10.1016/j.cmet.2017.08.002PMC PMC5762395

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Abstract

NAFLD is closely linked with hepatic insulin resistance. Accumulation of hepatic diacylglycerol activates PKC-ε, impairing insulin receptor activation and insulin-stimulated glycogen synthesis. Peripheral insulin resistance indirectly influences hepatic glucose and lipid metabolism by increasing flux of substrates that promote lipogenesis (glucose and fatty acids) and gluconeogenesis (glycerol and fatty acid-derived acetyl-CoA, an allosteric activator of pyruvate carboxylase). Weight loss with diet or bariatric surgery effectively treats NAFLD, but drugs specifically approved for NAFLD are not available. Some new pharmacological strategies act broadly to alter energy balance or influence pathways that contribute to NAFLD (e.g., agonists for PPAR γ, PPAR α/δ, FXR and analogs for FGF-21, and GLP-1). Others specifically inhibit key enzymes involved in lipid synthesis (e.g., mitochondrial pyruvate carrier, acetyl-CoA carboxylase, stearoyl-CoA desaturase, and monoacyl- and diacyl-glycerol transferases). Finally, a novel class of liver-targeted mitochondrial uncoupling agents increases hepatocellular energy expenditure, reversing the metabolic and hepatic complications of NAFLD.

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Authors: Samuel, V. T., & Shulman, G. I.
Affiliations: United States Department of Veterans Affairs (US)
Howard Hughes Medical Institute (US)
Corresponding author: Samuel, Varman T.
Shulman, Gerald I.
ORCID: Samuel, Varman T.
Shulman, Gerald I.
Venue: Cell Metabolism
Publisher: Elsevier BV
Published: 2018-01
Volume: 27
Issue: 1
Pages: 22-41
ISSN: 1550-4131 (ISSN-L)
DOI: 10.1016/j.cmet.2017.08.002
PMC: PMC5762395
OpenAlex: W2752428556
Cited by: 745
References: 263
Citations by year: 2026: 72 · 2025: 84 · 2024: 90 · 2023: 109 · 2022: 88 · 2021: 91 · 2020: 81 · 2019: 71 · 2018: 50
FWCI: 7.61
Type: journal article
Language: en
Open access: bronze
doi.org
Licence: www.elsevier.com/tdm/userlicense/1.0/ (tdm)
www.elsevier.com/legal/tdmrep-license (tdm)
www.elsevier.com/open-access/userlicense/1.0/ (vor, 374 d)
Locations: Cell Metabolism (publishedVersion)
PubMed (publishedVersion)
Europe PMC (PubMed Central) (acceptedVersion)
PubMed Central (acceptedVersion)
Funders: Celgene
Novo Nordisk
National Institutes of Health (DK-40936, DK-45735, DK-R01 DK 11398401)
AstraZeneca
Gilead Sciences
Merck
Topics: Health Sciences › Medicine › Hepatology › Liver Disease Diagnosis and Treatment
Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diet, Metabolism, and Disease
Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diabetes, Cardiovascular Risks, and Lipoproteins
Keywords: non-alcoholic fatty liver disease, hepatic insulin resistance, diacylglycerol, protein kinase C epsilon, insulin receptor, glycogen synthesis, lipogenesis, gluconeogenesis, pyruvate carboxylase, bariatric surgery, weight loss, PPAR agonists, farnesoid X receptor, FGF21, glucagon-like peptide-1, acetyl-CoA carboxylase, stearoyl-CoA desaturase, mitochondrial uncoupling, therapeutic target
MeSH terms: Animals, Glucose, Humans, Insulin, Insulin Resistance, Metabolic Diseases, Lipid Metabolism, Non-alcoholic Fatty Liver Disease

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Nonalcoholic Fatty Liver Disease as a Nexus of Metabolic and Hepatic Diseases

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