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

作者：Lin, Huige; Wang, Lin; Liu, Zhuohao; Long, Kekao; Kong, Mengjie; Ye, Dewei; Chen, Xi; Wang, Kai; Wu, Kelvin K. L.; Fan, Mengqi; Song, Erfei; Wang, Cunchuan; Hoo, Ruby L. C.; Hui, Xiaoyan; Hallenborg, Philip; Piao, Hailong; Xu, Aimin^*; Cheng, Kenneth K. Y.^*

来源：Advanced Science, 2022, 9(20): 2200742.

DOI：10.1002/advs.202200742

• apolipoprotein B (ApoB)
• murine double minute 2 (MDM2)
• metabolic associated fatty liver
• obesity
• triglyceride-VLDL

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.

• 单位
  1; 广东药学院; 南方医科大学; 中国科学院