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

• Published in: Journal of lipid research Vol. 62; p. 100031
• Main Authors: Xia, Mingfeng, Chandrasekaran, Preethi, Rong, Shunxing, Fu, Xiaorong, Mitsche, Matthew A.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01-01-2021; American Society for Biochemistry and Molecular Biology; Elsevier
• Subjects: fatty liver disease; flux analysis; lipidomics; liver-specific knockout; lysophosphatidylinositol acyltransferase 1; membrane-bound O-acyltransferase domain-containing 7; obesity; phosphatidylinositol; sterol regulatory element-binding protein 1c; NAFLD; DNL; GTT; ITT; dKO; MRM; IRS; fatty liver disease; sterol regulatory element-binding protein 1c; mTOR; membrane-bound O-acyltransferase domain-containing 7; liver-specific knockout; ASO; obesity; AA; ACC; flux analysis; MBOAT7; ACL; AKT; DAG; LPIAT; TM6sf2; TMC4; lysophosphatidylinositol acyltransferase 1; LPLAT; PC; TG; phosphatidylinositol; PE; PG; PNPLA3; Scap; PI; lipidomics
• ISSN: 0022-2275; 1539-7262; 1539-7262
• DOI: 10.1194/jlr.RA120000856

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.
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