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Cell Metab. 2018 Jan 9;27(1):22-41. doi: 10.1016/j.cmet.2017.08.002. Epub 2017 Aug 31.

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

Author information

1
Department of Medicine, Yale University School of Medicine, New Haven, CT 06510, USA; Veterans Affairs Medical Center, West Haven, CT 06516, USA. Electronic address: varman.samuel@yale.edu.
2
Department of Medicine, Yale University School of Medicine, New Haven, CT 06510, USA; Department of Cellular and Molecular Physiology, Yale University School of Medicine, New Haven, CT 06510, USA; Howard Hughes Medical Institute, Yale University School of Medicine, New Haven, CT 06510, USA. Electronic address: gerald.shulman@yale.edu.

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.

KEYWORDS:

diacylglycerol; insulin resistance; liver metabolism; mitochondria; non-alcoholic fatty liver disease; non-alcoholic steatohepatitis; type 2 diabetes

PMID:
28867301
PMCID:
PMC5762395
DOI:
10.1016/j.cmet.2017.08.002
[Indexed for MEDLINE]
Free PMC Article

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