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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.

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