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

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.