Oral Presentation Australian Diabetes Society and the Australian Diabetes Educators Association Annual Scientific Meeting 2016

The role of lipid droplet protein, Perilipin 5, in glucose and lipid metabolism (#66)

Stacey N Keenan 1 , Chi Y Lo 1 , Ruth C Meex 1 , Matthew J Watt 1
  1. Department of Physiology, Monash University, Clayton, Victoria, Australia

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. Initial studies were performed in cultured primary hepatocytes obtained from Plin5-/- mice and wild-type (Wt) control mice. Plin5-/- hepatocytes exhibited remarkable remodeling of lipid metabolism with decreased free fatty acid uptake and oxidation, and decreased triglyceride lipolysis and oxidation of intrahepatic triglyceride-derived fatty acids. Conversely, de novo lipogenesis and triglyceride secretion was increased in Plin5-/- compared with Wt hepatocytes. The net effect of these changes was a decrease in hepatic lipid content.

We next generated Plin5 liver-specific knockout mice (Plin5LKO) by crossing Plin5 flox/flox mice with albumin-Cre mice. 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. Studies in isolated livers demonstrated no significant differences in lipid metabolism between genotypes. Additionally, liver triglyceride content and histology were similar, and triglyceride secretion in conscious mice was unaffected by Plin5 deletion in the liver. Despite this, Plin5LKO mice are glucose intolerant and insulin resistant. When Plin5LKO mice are fed a high fat diet, a mild increase in overall body mass, fat mass and liver weight was observed. Ongoing studies will be directed at understanding the alternative mechanism at which PLIN5 is required to regulate normal glycemic control.