Mboat7 down-regulation by hyper-insulinemia induces fat accumulation in hepatocytes
Mboat7 down-regulation by hyper-insulinemia induces fat accumulation in hepatocytes
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DOI：
10.1016/j.ebiom.2020.102658
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发表时间：
2020-02-01
期刊：
影响因子：
11.1
通讯作者：
Valenti, Luca
中科院分区：
文献类型：
--
作者：
Meroni, Marica;Dongiovanni, Paola;Valenti, Luca
背景：膜结合O-酰基转移酶结构域7(MBOAT7)编码一种参与磷脂酰化肌醇酰链重塑的酶，其自然发生的变异与脂肪肝和肝脏疾病有关。在这里，我们研究了肝脏Mboat7下调与脂肪堆积的关系。方法：在119名肥胖者和实验模型中检测肝脏MBOAT7的表达。在C57B1/6小鼠中，反义寡核苷酸可显著沉默MBOAT7，在HepG2肝细胞中可被CRISPR/Cas9显著沉默。研究发现：在肥胖者中，肝脏中的MBOAT7基因表达水平从正常肝脏下降到脂肪性肝炎，与糖尿病、炎症和MBOAT7基因无关。在脂肪肝和高胰岛素血症小鼠模型中，肝脏MBOAT7水平降低。在野生型小鼠中，Mboat7被重新喂养和胰岛素下调，同时伴随着胰岛素信号的激活。急性肝Mboat7沉默促进体内肝脏脂肪变性，并增强脂肪酸转运体Fatp1的表达。肝细胞中MBOAT7的缺失减少了花生四烯酸对磷脂酰肌醇的掺入，与酶活性降低一致，决定了饱和甘油三酯的积累，促进了脂肪生成和FATP1的表达，而FATP1缺失挽救了表型。解释：高胰岛素血症下调MBOAT7有助于肝脏脂肪堆积，损害磷脂酰肌醇重塑和上调FATP1。(C)2020年提交人(S)。爱思唯尔出版公司(Elsevier B.V.)
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.