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 C57Bl/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. FUNDING LV was supported by MyFirst Grant AIRC n.16888, Ricerca Finalizzata Ministero della Salute RF-2016-02,364,358, Ricerca corrente Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico; LV and AG received funding from the European Union Programme Horizon 2020 (No. 777,377) for the project LITMUS-"Liver Investigation: Testing Marker Utility in Steatohepatitis". MM was supported by Fondazione Italiana per lo Studio del Fegato (AISF) 'Mario Coppo' fellowship.

中文翻译：

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高胰岛素血症引起的 Mboat7 下调诱导肝细胞中的脂肪积累。

背景技术天然存在的含膜结合O-酰基转移酶结构域7(MBOAT7)的变异，编码参与磷脂酰肌醇酰基链重塑的酶，与脂肪肝和肝脏疾病有关。在这里，我们检查了肝脏 Mboat7 下调与脂肪积累之间的关系。方法 在 119 名肥胖个体和实验模型中调查了肝脏 MBOAT7 的表达。MBOAT7 在 C57Bl/6 小鼠中被反义寡核苷酸急剧沉默，在 HepG2 肝细胞中被 CRISPR/Cas9 急剧沉默。结果 在肥胖个体中，肝脏 MBOAT7 mRNA 从正常肝脏下降为脂肪性肝炎，与糖尿病、炎症和 MBOAT7 基因型无关。在小鼠脂肪肝模型和高胰岛素血症中，肝脏 MBOAT7 水平降低。在野生型小鼠中，Mboat7 通过再喂养和胰岛素下调，同时伴随着胰岛素信号激活。急性肝 Mboat7 沉默促进体内肝脂肪变性并增强脂肪酸转运蛋白 Fatp1 的表达。肝细胞中的 MBOAT7 缺失减少了花生四烯酸与磷脂酰肌醇的结合，与酶活性降低一致，决定了饱和甘油三酯的积累，增强了脂肪生成和 FATP1 表达，而 FATP1 缺失挽救了表型。解释 高胰岛素血症导致 MBOAT7 下调有助于肝脏脂肪堆积，损害磷脂酰肌醇重塑和上调 FATP1。FUNDING LV 得到了 MyFirst Grant AIRC n.16888、Ricerca Finalizzata Ministero della Salute RF-2016-02,364,358、Ricerca corrente Fondazione IRCCS Ca' 的支持 Granda Ospedale Maggiore Policlinico；LV 和 AG 获得了欧盟项目 Horizo​​n 2020（编号 777,377）的资助，用于项目 LITMUS-“肝脏调查：在脂肪性肝炎中测试标记物效用”。MM 得到了 Fondazione Italiana per lo Studio del Fegato (AISF) 'Mario Coppo' 奖学金的支持。