Journal
JOURNAL OF LIPID RESEARCH
Volume 62, Issue -, Pages -Publisher
ELSEVIER
DOI: 10.1194/jlr.RA120000856
Keywords
fatty liver disease; phosphatidylinositol; obesity; lipidomics; flux analysis; membrane-bound O-acyltransferase domain-containing 7; lysophosphatidylinositol acyltransferase 1; sterol regulatory element-binding protein 1c; liver-specific knockout
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Funding
- National Heart, Lung, and Blood Institute [HL20948]
- National Institute of General Medical Sciences [GM137991]
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Recent identification of genetic variants that increase the risk of fatty liver disease and cirrhosis has led to the characterization of Mboat7 liver-specific KO mice in order to elucidate the link between these variants and fatty liver disease. The study revealed a relationship between fatty acid composition and regulation of hepatic fat synthesis, as well as delineated the mechanism by which mutations in MBOAT7 cause hepatic steatosis. 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.
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-lc, 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 n fatty acid composition and regulation of hepatic fat synthesis and delineates the mechanism by which mutations in MBOAT7 cause hepatic steatosis.
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