Hepatic Deletion of Mboat7 (Lpiat1) Causes Activation of SREBP-1c and Fatty Liver.

Genetic variants that increase the risk of fatty liver disease (FLD) 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 FLD we characterized Mboat7 liver-specific knock-out mice (Mboat7-LSKO).  Chow-fed Mboat7-LSKO mice developed fatty livers and associated liver injury.  Lipidomic analysis of liver using mass spectrometry revealed a pronounced reduction in 20-carbon polyunsaturated fatty acid 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 due to 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 knock-out showing 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.