Hepatic deletion of Mboat7 (LPIAT1) causes activation of SREBP-1c and fatty liver

Journal of Lipid Research

Preethi Chandrasekaran¹  Matthew A. Mitsche²  Xiaorong Fu³  Shunxing Rong³  Mingfeng Xia³ 

[1] Department of Endocrinology and Metabolism, Zhongshan Hospital, Fudan University, Shanghai, China;Department of Molecular Genetics, University of Texas Southwestern Medical Center, Dallas, TX, USA;Center for Human Nutrition, University of Texas Southwestern Medical Center, Dallas, TX, USA;

关键词: fatty liver disease;    phosphatidylinositol;    obesity;    lipidomics;    flux analysis;    membrane-bound O-acyltransferase domain-containing 7;   

DOI  :  

来源: DOAJ

【 摘 要 】

Abstract: Genetic variants that increase the risk of fatty liver disease and cirrhosis have recently been identified in the proximity of membrane-bound O-acyltransferase domain-containing 7 (MBOAT7). To elucidate the link between these variants and fatty liver disease, we characterized Mboat7 liver-specific KO mice (Mboat7 LSKO). Chow-fed Mboat7 LSKO mice developed fatty livers and associated liver injury. Lipidomic analysis of liver using MS revealed a pronounced reduction in 20-carbon PUFA content in phosphatidylinositols (PIs) but not in other phospholipids. The change in fatty acid composition of PIs in these mice was associated with a marked increase in de novo lipogenesis because of activation of SREBP-1c, a transcription factor that coordinates the activation of genes encoding enzymes in the fatty acid biosynthesis pathway. Hepatic removal of both SREBP cleavage-activating protein (Scap) and Mboat7 normalized hepatic triglycerides relative to Scap-only hepatic KO, showing that increased SREBP-1c processing is required for Mboat7-induced steatosis. This study reveals a clear relationship between PI fatty acid composition and regulation of hepatic fat synthesis and delineates the mechanism by which mutations in MBOAT7 cause hepatic steatosis.

【 授权许可】

Unknown