The Role of Hepatic MDM2 in the Regulation of Energy and Lipid Metabolism in Obesity

Abstract

IntroductionVery‐low‐density‐lipoprotein (VLDL) is a major vehicle for transporting lipids from liver to peripherals in plasma. VLDL‐triglyceride secretion is an important pathway for disposition of hepatic fat, and its inhibition results in hepatic steatosis. VLDL assembly and secretion are controlled by lipid availability and insulin resistance. MDM2, an E3 ligase mediating the final step of ubiquitination. We previously found that MDM2 regulates glucosestimulated insulin secretion via regulation of pyruvate carboxylase (PC) in the pancreatic islet. As PC is a key metabolic enzyme that mediates gluconeogenesis in the liver and MDM2 has been shown to control hepatic fatty acid oxidation. Therefore, we here investigated the role of MDM2 in hepatic energy and lipid metabolism using a hepatocyte‐specific MDM2 knockout mouse model.MethodsMDM2floxed/floxed mice were crossed with transgenic mice with Cre expression under the control of albumin promoter to generate hepatocyte‐specific MDM2 knockout (HMDM2‐ KO) mice. Mice were fed with a high‐fat‐high‐cholesterol (HFHC) diet for 16 weeks to induce obesity, insulin resistance and hepatic steatosis. Basic metabolic parameters and VLDL secretion rate were monitored.ResultsHepatocyte‐specific deletion of MDM2 has no obvious effect on body weight, insulin sensitivity, glucose tolerance and energy expenditure under HFHC diet feeding. HMDM2‐KO mice are characterized by postprandial hypertriglyceridemia, which results from increased hepatic VLDL secretion. Moreover, HMDM2‐KO mice displayed attenuated hepatic steatosis and downregulated mRNA and protein level of inflammatory markers in the liver when compared to their wild‐type littermates.ConclusionOur study proposes a novel role of hepatic MDM2 in regulation VLDL‐triglyceride secretion independent of insulin resistance.This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.