LPIAT1/MBOAT7 depletion increases triglyceride synthesis fueled by high phosphatidylinositol turnover.
LPIAT1/MBOAT7 depletion increases triglyceride synthesis fueled by high phosphatidylinositol turnover.
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DOI：
10.1136/gutjnl-2020-320646
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发表时间：
2021-01
期刊：
影响因子：
24.5
通讯作者：
Kono N
中科院分区：
文献类型：
--
作者：
Tanaka Y;Shimanaka Y;Caddeo A;Kubo T;Mao Y;Kubota T;Kubota N;Yamauchi T;Mancina RM;Baselli G;Luukkonen P;Pihlajamäki J;Yki-Järvinen H;Valenti L;Arai H;Romeo S;Kono N
非酒精性脂肪性肝病（NAFLD）是肝硬化和肝细胞癌的常见前奏。溶血磷脂酰肌醇酰基转移酶1（LPIAT 1）/膜结合O-酰基转移酶结构域7中的遗传rs641738 C>T变异体，将花生四烯酸掺入磷脂酰肌醇（PI）中，与NAFLD的整个谱相关。在这项研究中，我们研究了小鼠和培养的人肝细胞中这种关联的机制。我们建立了肝细胞特异性Lpiat 1基因敲除小鼠，以研究Lpiat 1在体内的功能。我们还使用CRISPR-Cas9系统或siRNA耗尽了培养的人肝细胞中的LPIAT 1。在喂食高脂肪饮食的小鼠和肝球状体中检查LPIAT 1消耗对肝纤维化的影响。使用液相色谱-电喷雾电离质谱法测量脂质种类。使用放射性标记的甘油或脂肪酸分析脂质代谢。肝细胞特异性Lpiat 1基因敲除小鼠自发发生肝脂肪变性，高脂饮食喂养后发生肝纤维化。培养的肝细胞和球状体中LPIAT 1的耗尽引起甘油三酯积累和胶原沉积。肝细胞脂肪含量的增加是由于非经典途径引起的甘油三酯合成增加。事实上，减少PI酰基链重塑引起高PI营业额，刺激在同一时间PI的合成和分解。PI的降解是由磷脂酶C介导的，磷脂酶C产生甘油二酯，甘油三酯的前体。我们发现了一种新的途径，通过PI直接代谢为甘油三酯，促进肝细胞中甘油三酯的合成。我们的研究结果提供了一个深入了解NAFLD的发病机制和治疗。
Non-alcoholic fatty liver disease (NAFLD) is a common prelude to cirrhosis and hepatocellular carcinoma. The genetic rs641738 C>T variant in the lysophosphatidylinositol acyltransferase 1 (LPIAT1)/membrane bound O-acyltransferase domain-containing 7, which incorporates arachidonic acid into phosphatidylinositol (PI), is associated with the entire spectrum of NAFLD. In this study, we investigated the mechanism underlying this association in mice and cultured human hepatocytes. We generated the hepatocyte-specific Lpiat1 knockout mice to investigate the function of Lpiat1 in vivo. We also depleted LPIAT1 in cultured human hepatic cells using CRISPR-Cas9 systems or siRNA. The effect of LPIAT1-depletion on liver fibrosis was examined in mice fed high fat diet and in liver spheroids. Lipid species were measured using liquid chromatography-electrospray ionisation mass spectrometry. Lipid metabolism was analysed using radiolabeled glycerol or fatty acids. The hepatocyte-specific Lpiat1 knockout mice developed hepatic steatosis spontaneously, and hepatic fibrosis on high fat diet feeding. Depletion of LPIAT1 in cultured hepatic cells and in spheroids caused triglyceride accumulation and collagen deposition. The increase in hepatocyte fat content was due to a higher triglyceride synthesis fueled by a non-canonical pathway. Indeed, reduction in the PI acyl chain remodelling caused a high PI turnover, by stimulating at the same time PI synthesis and breakdown. The degradation of PI was mediated by a phospholipase C, which produces diacylglycerol, a precursor of triglyceride. We found a novel pathway fueling triglyceride synthesis in hepatocytes, by a direct metabolic flow of PI into triglycerides. Our findings provide an insight into the pathogenesis and therapeutics of NAFLD.
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影响因子：
3.3
作者：
Lee HC;Inoue T;Sasaki J;Kubo T;Matsuda S;Nakasaki Y;Hattori M;Tanaka F;Udagawa O;Kono N;Itoh T;Ogiso H;Taguchi R;Arita M;Sasaki T;Arai H
通讯作者：
Arai H
影响因子：
29.4
作者：
Lambert JE;Ramos-Roman MA;Browning JD;Parks EJ
通讯作者：
Parks EJ
影响因子：
6.5
作者：
Millar, JS;Cromley, DA;Billheimer, JT
通讯作者：
Billheimer, JT
影响因子：
29.4
作者：
Mancina RM;Dongiovanni P;Petta S;Pingitore P;Meroni M;Rametta R;Borén J;Montalcini T;Pujia A;Wiklund O;Hindy G;Spagnuolo R;Motta BM;Pipitone RM;Craxì A;Fargion S;Nobili V;Käkelä P;Kärjä V;Männistö V;Pihlajamäki J;Reilly DF;Castro-Perez J;Kozlitina J;Valenti L;Romeo S
通讯作者：
Romeo S
影响因子：
11.1
作者：
Dongiovanni P;Stender S;Pietrelli A;Mancina RM;Cespiati A;Petta S;Pelusi S;Pingitore P;Badiali S;Maggioni M;Mannisto V;Grimaudo S;Pipitone RM;Pihlajamaki J;Craxi A;Taube M;Carlsson LMS;Fargion S;Romeo S;Kozlitina J;Valenti L
通讯作者：
Valenti L