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. Initial in vitro studies were performed in cultured primary hepatocytes obtained from Plin5LKO mice and wild-type (Wt) control mice. Plin5LKO hepatocytes exhibited remarkable remodeling of lipid metabolism with decreased free fatty acid uptake and oxidation, as well as decreased triglyceride lipolysis and oxidation of intrahepatic triglyceride-derived fatty acids. Equally, de novo lipogenesis and triglyceride secretion was decreased in Plin5LKO compared with Wt hepatocytes.
In vivo studies show that Plin5LKO mice fed a chow diet have similar body mass, body composition, whole-body substrate oxidation rate and blood lipid profiles. When Plin5LKO mice were fed a high fat diet, a mild increase in overall body mass, fat mass and liver weight was observed. Additionally, liver triglyceride content and liver damage (ALT) was considerably increased. Hyperinsulinemic-euglycemic clamp studies demonstrated decreased glucose infusion rate and an inability to suppress hepatic glucose production during insulin stimulation in Plin5LKO mice. Ongoing studies will be directed at understanding how PLIN5 deficiency causes hepatic insulin resistance.