Nicholls Hayley T, Hornick Jason L, Cohen David E
Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts; and.
Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts.
Am J Physiol Gastrointest Liver Physiol. 2017 Jul 1;313(1):G50-G61. doi: 10.1152/ajpgi.00379.2016. Epub 2017 Apr 6.
Mice fed a methionine- and choline-deficient (MCD) diet develop steatohepatitis that recapitulates key features of nonalcoholic steatohepatitis (NASH) in humans. Phosphatidylcholine is the most abundant phospholipid in the surfactant monolayer that coats and stabilizes lipid droplets within cells, and choline is required for its major biosynthetic pathway. Phosphatidylcholine-transfer protein (PC-TP), which exchanges phosphatidylcholines among membranes, is enriched in hepatocytes. PC-TP also regulates fatty acid metabolism through interactions with thioesterase superfamily member 2. We investigated the contribution of PC-TP to steatohepatitis induced by the MCD diet. and wild-type control mice were fed the MCD diet for 5 wk and were then euthanized for histopathologic and biochemical analyses, as well as determinations of mRNA and protein expression. Whereas all mice developed steatohepatitis, plasma alanine aminotransferase and aspartate aminotransferase activities were only elevated in wild-type mice, indicating that mice were protected from MCD diet-induced hepatocellular injury. Reduced hepatotoxicity due to the MCD diet in the absence of PC-TP expression was further evidenced by decreased activation of c-Jun and reduced plasma concentrations of fibroblast growth factor 21. Despite similar total hepatic concentrations of phosphatidylcholines and other lipids, the relative abundance of microvesicular lipid droplets within hepatocytes was reduced in mice. Considering that the formation of larger lipid droplets may serve to protect against lipotoxicity in NASH, our findings suggest a pathogenic role for PC-TP that could be targeted in the management of this condition. Phosphatidylcholine-transfer protein (PC-TP) is a highly specific phosphatidylcholine-binding protein that we previously showed to regulate hepatocellular nutrient metabolism through its interacting partner thioesterase superfamily member 2 (Them2). This study identifies a pathogenic role for PC-TP, independent of Them2, in the methionine- and choline-deficient diet model of experimental steatohepatitis. Our current observations suggest that PC-TP promotes liver injury by mediating the intermembrane transfer of phosphatidylcholines, thus stabilizing more pathogenic microvesicular lipid droplets.
喂食蛋氨酸和胆碱缺乏（MCD）饮食的小鼠会发展出脂肪性肝炎，其重现了人类非酒精性脂肪性肝炎（NASH）的关键特征。磷脂酰胆碱是包裹并稳定细胞内脂质滴的表面活性剂单层中最丰富的磷脂，胆碱是其主要生物合成途径所必需的。在膜之间交换磷脂酰胆碱的磷脂酰胆碱转移蛋白（PC-TP）在肝细胞中富集。PC-TP还通过与硫酯酶超家族成员2相互作用来调节脂肪酸代谢。我们研究了PC-TP对MCD饮食诱导的脂肪性肝炎的作用。将PC-TP基因敲除小鼠和野生型对照小鼠喂食MCD饮食5周，然后实施安乐死以进行组织病理学和生化分析，以及测定mRNA和蛋白质表达。虽然所有小鼠都发展出了脂肪性肝炎，但血浆丙氨酸转氨酶和天冬氨酸转氨酶活性仅在野生型小鼠中升高，这表明PC-TP基因敲除小鼠免受MCD饮食诱导的肝细胞损伤。c-Jun激活减少和成纤维细胞生长因子21血浆浓度降低进一步证明了在没有PC-TP表达的情况下，MCD饮食导致的肝毒性降低。尽管肝细胞中磷脂酰胆碱和其他脂质的总浓度相似，但PC-TP基因敲除小鼠肝细胞内微泡脂质滴的相对丰度降低。考虑到更大脂质滴的形成可能有助于预防NASH中的脂毒性，我们的研究结果表明PC-TP在这种疾病的管理中可能是一个可靶向的致病因素。磷脂酰胆碱转移蛋白（PC-TP）是一种高度特异性的磷脂酰胆碱结合蛋白，我们之前表明它通过其相互作用伙伴硫酯酶超家族成员2（Them-2）调节肝细胞营养代谢。本研究确定了PC-TP在实验性脂肪性肝炎的蛋氨酸和胆碱缺乏饮食模型中独立于Them-2的致病作用。我们目前的观察结果表明PC-TP通过介导磷脂酰胆碱的膜间转移来促进肝损伤，从而稳定更多致病性的微泡脂质滴。
