The ratio of phosphatidylcholine to phosphatidylethanolamine influences membrane integrity and steatohepatitis
The ratio of phosphatidylcholine to phosphatidylethanolamine influences membrane integrity and steatohepatitis
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DOI：
10.1016/j.cmet.2006.03.007
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发表时间：
2006-05-01
期刊：
影响因子：
29
通讯作者：
Vance, Dennis E.
中科院分区：
文献类型：
--
作者：
Li, Zhaoyu;Agellon, Luis B.;Vance, Dennis E.
磷脂酰胆碱（PC）和磷脂酰乙醇胺（PE）是哺乳动物细胞膜中的主要磷脂。在肝脏中，PC通过胆碱途径或通过磷脂酰乙醇胺N-甲基转移酶（PEMT）甲基化PE合成。喂食胆碱缺乏（CD）饮食的Pemt（-/-）小鼠发生快速脂肪性肝炎，导致肝功能衰竭。在缺乏PEMT和多药耐药蛋白2（MDR 2）的CD小鼠中观察到脂肪变性，这是PC分泌到胆汁中所需的。我们证明，在CD-Pemt（-/-）小鼠的肝衰竭是由于PC/PE比下降引起的膜完整性的损失。CD-Mdr 2（-/-）/Pemt（-/-）小鼠通过维持正常的PC/PE比率来逃避肝衰竭。PC/PE水平的操纵表明，该比例是细胞膜完整性的关键调节因子，并在脂肪变性进展为脂肪性肝炎中发挥作用。结果具有临床意义，因为与对照肝脏相比，非酒精性脂肪性肝炎患者PC与PE的比率降低。
Phosphatidylcholine (PC) and phosphatidylethanolamine (PE) are major phospholipids in mammalian membranes. In liver, PC is synthesized via the choline pathway or by methylation of PE via phosphatidylethanolamine N-methyltransferase (PEMT). Pemt(-/-) mice fed a choline-deficient (CD) diet develop rapid steatohepatitis leading to liver failure. Steatosis is observed in CD mice that lack both PEMT and multiple drug-resistant protein 2 (MDR2), required for PC secretion into bile. We demonstrate that liver failure in CD-Pemt(-/-) mice is due to loss of membrane integrity caused by a decreased PC/PE ratio. The CD-Mdr2(-/-)/Pemt(-/-) mice escape liver failure by maintaining a normal PC/PE ratio. Manipulation of PC/PE levels suggests that this ratio is a key regulator of cell membrane integrity and plays a role in the progression of steatosis into steatohepatitis. The results have clinical implications as patients with nonalcoholic steatohepatitis have a decreased ratio of PC to PE compared to control livers.