Hepatic MDM2 Causes Metabolic Associated Fatty Liver Disease by Blocking Triglyceride-VLDL Secretion via ApoB Degradation

Adv Sci (Weinh). 2022 Jul;9(20):e2200742. doi: 10.1002/advs.202200742. Epub 2022 May 7.

Abstract

Dysfunctional triglyceride-very low-density lipoprotein (TG-VLDL) metabolism is linked to metabolic-associated fatty liver disease (MAFLD); however, the underlying cause remains unclear. The study shows that hepatic E3 ubiquitin ligase murine double minute 2 (MDM2) controls MAFLD by blocking TG-VLDL secretion. A remarkable upregulation of MDM2 is observed in the livers of human and mouse models with different levels of severity of MAFLD. Hepatocyte-specific deletion of MDM2 protects against high-fat high-cholesterol diet-induced hepatic steatosis and inflammation, accompanied by a significant elevation in TG-VLDL secretion. As an E3 ubiquitin ligase, MDM2 targets apolipoprotein B (ApoB) for proteasomal degradation through direct protein-protein interaction, which leads to reduced TG-VLDL secretion in hepatocytes. Pharmacological blockage of the MDM2-ApoB interaction alleviates dietary-induced hepatic steatohepatitis and fibrosis by inducing hepatic ApoB expression and subsequent TG-VLDL secretion. The effect of MDM2 on VLDL metabolism is p53-independent. Collectively, these findings suggest that MDM2 acts as a negative regulator of hepatic ApoB levels and TG-VLDL secretion in MAFLD. Inhibition of the MDM2-ApoB interaction may represent a potential therapeutic approach for MAFLD treatment.

Keywords: apolipoprotein B (ApoB); metabolic associated fatty liver; murine double minute 2 (MDM2); obesity; triglyceride-VLDL.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Apolipoproteins B* / metabolism
  • Fatty Liver* / etiology
  • Fatty Liver* / metabolism
  • Humans
  • Lipoproteins, VLDL* / metabolism
  • Liver* / metabolism
  • Mice
  • Obesity* / complications
  • Proteolysis
  • Proto-Oncogene Proteins c-mdm2* / metabolism
  • Triglycerides* / metabolism

Substances

  • Apolipoproteins B
  • Lipoproteins, VLDL
  • Triglycerides
  • MDM2 protein, human
  • Mdm2 protein, mouse
  • Proto-Oncogene Proteins c-mdm2