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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.

Graphical abstract

Titel:	Hepatic deletion of Mboat7 (LPIAT1) causes activation of SREBP-1c and fatty liver
Autor/in / Beteiligte Person:	Rong, Shunxing ; Fu, Xiaorong ; Mitsche, Matthew A. ; Xia, Mingfeng ; Chandrasekaran, Preethi
Link:	View record in OpenAIRE (Volltext) https://pubmed.ncbi.nlm.nih.gov/32859645
Zeitschrift:	Journal of lipid research, Jg. 62 (2020-04-23)
Veröffentlichung:	2020
Medientyp:	unknown
ISSN:	1539-7262 (print)
Schlagwort:	0301 basic medicine phosphatidylinositol obesity ACL, ATP citrate lyase AA, arachidonic acid ACC, acetyl-CoA carboxylase 030204 cardiovascular system & hematology PG, phosphatidylglycerol Biochemistry chemistry.chemical_compound PC, phosphatidylcholine 0302 clinical medicine Endocrinology DAG, diacylglyceride liver-specific knockout flux analysis chemistry.chemical_classification Liver injury LPIAT, lysophosphatidylinositol acyltransferase biology TMC4, transmembrane channel 4 TG, triglyceride SREBP cleavage-activating protein Fatty liver LPLAT, lysophospholipid acyltransferase Lipogenesis IRS, insulin receptor substrate dKO, double KO GTT, glucose tolerance test Arachidonic acid MBOAT7, membrane-bound O-acyltransferase domain-containing 7 Sterol Regulatory Element Binding Protein 1 Polyunsaturated fatty acid Research Article medicine.medical_specialty NAFLD, non-alcoholic fatty liver disease PNPLA3, patatin-like phospholipase domain-containing 3 TM6sf2, transmembrane 6 superfamily member 2 QD415-436 DNL, de novo lipogenesis mTOR, mammalian target of rapamycin PE, phosphatidylethanolamine AKT, protein kinase B PI, phosphatidylinositol 03 medical and health sciences Internal medicine medicine sterol regulatory element-binding protein 1c ITT, insulin tolerance test Triglyceride Scap, SREBP cleavage-activating protein membrane-bound O-acyltransferase domain-containing 7 Cell Biology medicine.disease ASO, anti-sense oligonucleotide 030104 developmental biology chemistry lysophosphatidylinositol acyltransferase 1 biology.protein fatty liver disease lipidomics Steatosis MRM, multiple reaction monitoring
Sonstiges:	Nachgewiesen in: OpenAIRE Rights: OPEN

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