Abstract
AbstractGenetic 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.
Highlights
Genetic variants that increase the risk of fatty liver disease and cirrhosis have recently been identified in the proximity of membrane-bound Oacyltransferase domain-containing 7 (MBOAT7)
The adjacent Tmc4 and closely related Mboat5 (Lpcat3) mRNA levels were not altered in Mboat7 LSKO livers
To determine whether inactivation of Mboat7 in the liver causes hepatic steatosis by increasing the rate of de novo lipogenesis (DNL), we examined the mRNA levels of genes encoding enzymes involved in fatty acid and sterol synthesis
Summary
Genetic variants that increase the risk of fatty liver disease and cirrhosis have recently been identified in the proximity of membrane-bound Oacyltransferase domain-containing 7 (MBOAT7). 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 Mboat normalized hepatic triglycerides relative to Scap-only hepatic KO, showing that increased SREBP-1c processing is required for Mboat7-induced steatosis. Both MBOAT5 and MBOAT7 have lysophospholipid acyltransferase (LPLAT) activity where they incorporate Ω-6 fatty acids into the sn-2 position of
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