The role of MDM2 in hepatic lipid metabolism

Abstract

Background and objective: Liver is a core organ in regulation of lipid homeostasis, which is vital for life and health. Obesity is closely associated with dyslipidemia, but the molecular mechanism remains poorly understood. Insulin resistance is the major pathogenic condition of metabolic syndrome, which links obesity with serum lipidemia and non-alcohol fatty liver disease (NAFLD). MDM2 is an E3 ubiquitin ligase that mediates degradation of the tumor suppressor p53. In addition to its tumor suppressive functions, p53 has been shown to regulate numerous pathways related to glucose and lipid metabolism. In particular, we recently demonstrated that the MDM2-p53 signaling axis is crucial for glucose-stimulated insulin secretion in pancreatic beta cells, and dysregulation of this axis causes glucose intolerance in mice. Our preliminary data indicated that expression of MDM2 is dramatically induced in the liver of obese mice, suggesting that MDM2 may involve in regulation of liver function in response to nutrient stress. In this study, we employed a hepatocyte-specific MDM2 knockout (MDM2 KO) mouse model to investigate the physiological and pathophysiological role of MDM2 in hepatic metabolism.

Key findings: 1. We successfully generated a hepatocyte-specific MDM2 knockout mouse model and confirmed that protein expression of MDM2 was reduced, but p53 was induced in mice with hepatic deletion of MDM2. Dietary-induced obesity was aggravated in MDM2 KO mice when compared to its wild type (WT) controls, despite their food intake, locomotor activity and energy expenditure were similar. 2. Glucose tolerance, insulin sensitivity, and gluconeogenesis were similar between MDM2 KO mice and its WT controls, as determined by glucose tolerance test, insulin tolerance test, and pyruvate tolerance test, respectively. 3. Although MDM2 KO mice displayed normal lipid metabolism under standard chow feeding, they developed postprandial hypertriglyceridemia upon challenge with high-fat high cholesterol (HFHC) diet for 16 weeks. Further studies revealed that the postprandial hypertriglyceridemia may be due to increased secretion of triglyceride-rich very low density lipoprotein (VLDL) and reduced triglyceride clearance. qPCR analysis demonstrated that genes related to VLDL metabolism such as ApoB (Apolipoprotein B), MTP (Microsomal triglyceride transfer protein) and FGF21 (Fibroblast growth factor 21) were altered in MDM2 KO mice fed with HFHC diet when compared its WT controls. 4. Fasting-induced ketogenesis but not lipolysis was impaired in MDM2 KO mice. Consistently, ketogenesis induced by intraperitoneal injection of octanoic acid was diminished in MDM2 KO mice when compared to WT controls. The defective ketogenesis in MDM2 KO mice was associated with aberrant mRNA expression of genes related to ketogenesis including HMGCS2 (3-hydroxy-3-methylglutaryl- CoA synthase 2), HMGCL (3-hydroxymethyl-3-methylglutaryl-CoA lyase), and BDH1 (3-hydroxybutyrate dehydrogenase, type 1) in the liver.

Conclusion: Our results collectively demonstrate that hepatic MDM2 is a key determinant of triglyceride metabolism and ketogenesis under obese condition. These findings suggested MDM2 can be potentially used as a target for future development of new strategies for treating and preventing dyslipidemia in obesity.