期刊
EBIOMEDICINE
卷 52, 期 -, 页码 -出版社
ELSEVIER
DOI: 10.1016/j.ebiom.2020.102658
关键词
LPIAT1; NAFLD; Nash; Nonalcoholic fatty liver disease; Steatohepatitis; Phospholipid; Phosphatidylinositol
资金
- MyFirst Grant AIRC [16888]
- Ricerca Finalizzata Ministero della Salute [RF-2016-02364358, RF-2013-02358519]
- Ricerca corrente Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico
- European Union (EU) Programme Horizon 2020 [777377, 634413]
- Fondazione Italiana per lo Studio del Fegato (AISF) 'Prof. Mario Coppo' fellowship
Background: Naturally occurring variation in Membrane-bound O-acyltransferase domain-containing 7 (MBOAT7), encoding for an enzyme involved in phosphatidylinositol acyl-chain remodelling, has been associated with fatty liver and hepatic disorders. Here, we examined the relationship between hepatic Mboat7 down-regulation and fat accumulation. Methods: Hepatic MBOAT7 expression was surveyed in 119 obese individuals and in experimental models. MBOAT7 was acutely silenced by antisense oligonucleotides in C57B1/6 mice, and by CRISPR/Cas9 in HepG2 hepatocytes. Findings: In obese individuals, hepatic MBOAT7 mRNA decreased from normal liver to steatohepatitis, independently of diabetes, inflammation and MBOAT7 genotype. Hepatic MBOAT7 levels were reduced in murine models of fatty liver, and by hyper-insulinemia. In wild-type mice, Mboat7 was down-regulated by refeeding and insulin, concomitantly with insulin signalling activation. Acute hepatic Mboat7 silencing promoted hepatic steatosis in vivo and enhanced expression of fatty acid transporter Fatp1. MBOAT7 deletion in hepatocytes reduced the incorporation of arachidonic acid into phosphatidylinositol, consistently with decreased enzymatic activity, determining the accumulation of saturated triglycerides, enhanced lipogenesis and FATP1 expression, while FATP1 deletion rescued the phenotype. Interpretation: MBOAT7 down-regulation by hyper-insulinemia contributes to hepatic fat accumulation, impairing phosphatidylinositol remodelling and up-regulating FATP1. (C) 2020 The Author(s). Published by Elsevier B.V.
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