Obesity is associated with dysfunctions in lipid and glucose metabolism, which is linked to the development of insulin resistance and type 2 diabetes. The perilipin (PLIN) family of proteins localize to cellular lipid droplets and control lipid flux within cells by coordinating protein-protein interactions. PLIN5 is expressed in highly oxidative tissues and, in skeletal muscle, controls triglyceride lipolysis and β-oxidation of fatty acids, which in turn helps to maintain insulin sensitivity in this tissue.
The aim of this study was to investigate the role of PLIN5 in regulating hepatic lipid and glucose metabolism in lean and obese mice. To address this aim, we generated PLIN5 liver-specific knockout mice (Plin5LKO) by crossing Plin5 floxed mice with albumin-Cre mice. 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.