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CRISPR-mediated BMP9 ablation promotes liver steatosis via the down-regulation of PPARα expression.

Authors
  • Yang, Z1, 2, 3
  • Li, P1, 3
  • Shang, Q1, 3
  • Wang, Y1, 3
  • He, J1, 3
  • Ge, S4, 3
  • Jia, R4, 3
  • Fan, X4, 2, 3
  • 1 Department of Ophthalmology, Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, 833 Zhizaoju Road, Shanghai 200011, China. , (China)
  • 2 CAS Key Laboratory of Tissue Microenvironment and Tumor, Shanghai Institute of Nutrition and Health, Shanghai Institutes for Biological Sciences, University of Chinese Academy of Sciences, Chinese Academy of Sciences, 320 Yueyang Road, Shanghai 200032, China. , (China)
  • 3 Shanghai Key Laboratory of Orbital Diseases and Ocular Oncology, 833 Zhizaoju Road, Shanghai 200011, China. , (China)
  • 4 Department of Ophthalmology, Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, 833 Zhizaoju Road, Shanghai 200011, China. [email protected] [email protected] [email protected] , (China)
Type
Published Article
Journal
Science Advances
Publisher
American Association for the Advancement of Science (AAAS)
Publication Date
Nov 01, 2020
Volume
6
Issue
48
Identifiers
DOI: 10.1126/sciadv.abc5022
PMID: 33246954
Source
Medline
Language
English
License
Unknown

Abstract

Obesity drives the development of nonalcoholic fatty liver disease (NAFLD) characterized by hepatic steatosis. Several bone morphogenetic proteins (BMPs) except BMP9 were reported related to metabolic syndrome. This study demonstrates that liver cytokine BMP9 is decreased in the liver and serum of NAFLD model mice and patients. BMP9 knockdown induces lipid accumulation in Hepa 1-6 cells. BMP9-knockout mice exhibit hepatosteatosis due to down-regulated peroxisome proliferator-activated receptor α (PPARα) expression and reduced fatty acid oxidation. In vitro, recombinant BMP9 treatment attenuates triglyceride accumulation by enhancing PPARα promoter activity via the activation of p-smad. PPARα-specific antagonist GW6471 abolishes the effect of BMP9 knockdown. Furthermore, adeno-associated virus-mediated BMP9 overexpression in mouse liver markedly relieves liver steatosis and obesity-related metabolic syndrome. These findings indicate that BMP9 plays a critical role in regulating hepatic lipid metabolism in a PPARα-dependent manner and may provide a previously unknown insight into NAFLD therapeutic approaches. Copyright © 2020 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works. Distributed under a Creative Commons Attribution NonCommercial License 4.0 (CC BY-NC).

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