Endocrine Abstracts (2016) 41 GP132 | DOI: 10.1530/endoabs.41.GP132

The E3 ubiquitin ligase MDM2 acts as a key determinant of hepatic VLDL-triglycerides and ketone body production in obesity

Zhuohao Liu1,2, Aimin Xu1,2 & Kenneth K Y Cheng1,2

1The University of Hong Kong, Hong Kong, Hong Kong; 2State Key Laboratory of Pharmaceutical Biotechnology, Hong Kong, Hong Kong.

Introduction: Obesity is a major risk factor for the development of hyperlipidemia and its related cardiovascular complications. Apart from its well-established role in cancer biology, the MDM2-p53 axis has been recently shown to regulate glucose and lipid metabolism. Our preliminary data indicated that MDM2 is dramatically induced in the liver of obese mice. In this study, we aimed to investigate the potential role of hepatic MDM2 in controlling systemic lipid homeostasis using a hepatocyte-specific MDM2 knockout (H-MDM2KO) mouse model.

Method: H-MDM2KO mice were generated by crossing MDM2floxed mice with transgenic mice expressing Cre recombinase under the control of albumin promoter. Eight-week-old male H-MDM2KO mice and its WT littermates were fed with a standard chow or a high fat high cholesterol (HFHC) diet for 24 weeks. Lipid metabolism and energy metabolism were measured during the 24-week monitoring period.

Results: Genetic deletion of hepatic MDM2 led to elevation of p53 level in the liver. H-MDM2KO mice and WT controls displayed similar body weight, lipid profile and energy metabolism under standard chow feeding. Despite of similar body weight and food intake, H-MDM2KO mice exacerbated obesity-induced hypertriglyceridemia and impaired fasting-induced ketogenesis when fed with HFHC. The elevated triglyceride levels in H-MDM2KO mice was due to VLDL-triglyceride production, whereas intestinal chylomicron-triglyceride synthesis or VLDL-triglyceride clearance were normal. QPCR analysis revealed that the genes involved in VLDL assembly such as ApoB and ketogenesis (HMGCL and HMGCS2) were upregulated in the liver of H-MDM2KO mice, whereas genes involved fatty acid oxidation (PPAR-alpha, MCAD and CPT1a) and lipogenesis (SCREBP1c and Lipin-1) were unchanged when compared to its WT controls.

Conclusion: Our results indicated that MDM2 is a key player in controlling VLDL-triglyceride secretion and ketogenesis, thereby maintaining lipid homeostasis. We will further investigate whether these MDM2 actions are mediated by p53 in the future.

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