Defects in hepatic lipid metabolism cause non-alcoholic fatty liver disease and insulin resistance, and these pathologies are closely linked. Regulation of lipid droplet metabolism is central to the control of intracellular fatty acid fluxes and perilipin (PLIN) 5 is important in this process. We examined the role of PLIN5 on hepatic lipid metabolism and systemic glycemic control using liver-specific Plin5 deficient mice (Plin5LKO). Hepatocytes isolated from Plin5LKO mice exhibited marked changes in lipid metabolism characterized by decreased fatty acid uptake and storage, decreased fatty acid oxidation that was associated with reduced contact between lipid droplets and mitochondria, and reduced triglyceride secretion. With consumption of a high-fat diet, Plin5LKO mice accumulated intrahepatic triglyceride, without significant changes in inflammation, ceramide or diacylglycerol contents, endoplasmic reticulum stress or autophagy. Instead, livers of Plin5LKO mice exhibited activation of c-Jun N-terminal kinase, impaired insulin signal transduction and insulin resistance, which impaired systemic insulin action and glycemic control. Re-expression of Plin5 in the livers of Plin5LKO mice reversed these effects. Together, we show that Plin5 is an important modulator of intrahepatic lipid metabolism and suggest that the increased Plin5 expression that occurs with over nutrition may play an important role in preventing hepatic insulin resistance.

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