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


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 ? (PPAR?) expression and reduced fatty acid oxidation. In vitro, recombinant BMP9 treatment attenuates triglyceride accumulation by enhancing PPAR? promoter activity via the activation of p-smad. PPAR?-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 PPAR?-dependent manner and may provide a previously unknown insight into NAFLD therapeutic approaches.

SUBMITTER: Yang Z 

PROVIDER: S-EPMC7695473 | biostudies-literature | 2020 Nov

REPOSITORIES: biostudies-literature

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

Yang Z Z   Li P P   Shang Q Q   Wang Y Y   He J J   Ge S S   Jia R R   Fan X X  

Science advances 20201127 48


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  ...[more]

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