Please use this identifier to cite or link to this item:
http://hdl.handle.net/10397/94311
Title: | Hepatic MDM2 causes metabolic associated fatty liver disease by blocking triglyceride-VLDL secretion via ApoB degradation | Authors: | Lin, H Wang, L Liu, Z Long, K Kong, M Ye, D Chen, X Wang, K Wu, KKL Fan, M Song, E Wang, C Hoo, RLC Hui, X Hallenborg, P Piao, H Xu, A Cheng, KKY |
Issue Date: | Jul-2022 | Source: | Advanced science, 15 July 2022, v. 9, no. 20, 2200742 | 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 |
Publisher: | Wiley-VCH | Journal: | Advanced science | ISSN: | 2198-3844 | DOI: | 10.1002/advs.202200742 | Rights: | © 2022 The Authors. Advanced Science published by Wiley-VCH GmbH. This is an open access article under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/), which permits use, distribution and reproduction in any medium, provided the original work is properly cited. The following publication Lin, H., Wang, L., Liu, Z., Long, K., Kong, M., Ye, D., ... & Cheng, K. K. (2022). Hepatic MDM2 Causes Metabolic Associated Fatty Liver Disease by Blocking Triglyceride‐VLDL Secretion via ApoB Degradation. Advanced Science, 9(20), 2200742 is available at https://doi.org/10.1002/advs.202200742 |
Appears in Collections: | Journal/Magazine Article |
Files in This Item:
File | Description | Size | Format | |
---|---|---|---|---|
Lin_Hepatic_Metabolic_Associated.pdf | 6.52 MB | Adobe PDF | View/Open |
Page views
63
Last Week
0
0
Last month
Citations as of May 5, 2024
Downloads
281
Citations as of May 5, 2024
SCOPUSTM
Citations
6
Citations as of Apr 4, 2024
WEB OF SCIENCETM
Citations
6
Citations as of May 2, 2024
Google ScholarTM
Check
Altmetric
Items in DSpace are protected by copyright, with all rights reserved, unless otherwise indicated.