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

Publication date: Available online 31 August 2017
Source:Cell Metabolism
Author(s): Varman T. Samuel, Gerald I. Shulman
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.

Teaser

Nonalcoholic fatty liver disease (NAFLD) affects one in three Americans and predisposes to metabolic, liver, and cardiovascular disease. Weight loss, bariatric surgery, pioglitazone, and GLP1 analogs resolve NAFLD in some patients. Samuel and Shulman discuss promising novel therapies targeting hepatic lipogenesis, hepatic fat oxidation, whole-body energy balance, and liver-specific energy metabolism.


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