Hepatic deletion of Mboat7 (LPIAT1) causes activation of SREBP-1c and fatty liver.
Hepatic deletion of Mboat7 (LPIAT1) causes activation of SREBP-1c and fatty liver.
复制标题
DOI：
10.1194/jlr.ra120000856
复制
发表时间：
2021
影响因子：
6.5
通讯作者：
Mitsche MA
中科院分区：
文献类型：
--
作者：
Xia M;Chandrasekaran P;Rong S;Fu X;Mitsche MA
最近在膜结合O-酰基转移酶结构域7（MBOAT 7）附近发现了增加脂肪肝和肝硬化风险的遗传变异。为了阐明这些变异与脂肪肝疾病之间的联系，我们表征了Mboat 7肝脏特异性KO小鼠（Mboat 7 LSKO）。Chow喂养的Mboat 7 LSKO小鼠出现脂肪肝和相关的肝损伤。使用MS对肝脏进行的脂质组学分析显示，磷脂酰肌醇（PI）中的20-碳PUFA含量显著降低，但其他磷脂中的含量没有降低。这些小鼠中PI的脂肪酸组成的变化与新生脂肪生成的显著增加相关，这是由于SREBP-1c的激活，SREBP-1c是一种协调脂肪酸生物合成途径中编码酶的基因激活的转录因子。相对于仅Scap的肝KO，肝去除SREBP裂解激活蛋白（Scap）和Mboat 7使肝甘油三酯正常化，表明Mboat 7诱导的脂肪变性需要增加的SREBP-1c加工。这项研究揭示了PI脂肪酸组成和肝脏脂肪合成调节之间的明确关系，并描绘了MBOAT 7突变导致肝脏脂肪变性的机制。
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.