Hepatic MDM2 causes metabolic associated fatty liver disease by blocking triglyceride-VLDL secretion via ApoB degradation

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

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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.

OriginalsprogEngelsk
Artikelnummere2200742
TidsskriftAdvanced Science
Vol/bind9
Udgave nummer20
ISSN2198-3844
DOI
StatusUdgivet - 15. jul. 2022

Bibliografisk note

Funding Information:
The authors thank Prof. Guillermina Lozano (The University of Texas M.D. Anderson Cancer Center) for providing mice. They also thank Dr. Edward Yeh (University of Texas M.D. Anderson Cancer Center) for providing plasmids encoding HA‐ubiquitin and its mutants. They also thank Dr. Zemin Yao (University of Ottawa) for his professional advice on the detection of ApoB protein in liver tissues and providing the ApoB constructs. The authors thank the technical support from University Research Facility in Life Sciences (PolyU). This study was supported by Hong Kong Health Medical Research Fund (0 516 1286), National Natural Science Foundation of China (NSFC) (91 857 119), Hong Kong Research Grant Council (RGC) General Research Fund (17 100 717), Collaborative Research Fund (C7037‐17W), RGC Area of Excellence (AoE/M‐707/18), and Shenzhen Municipal Science and Technology Innovation Commission Basic Research General Programme: 20210324130202006. MDM2 floxed/floxed

Publisher Copyright:
© 2022 The Authors. Advanced Science published by Wiley-VCH GmbH.

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