Targeted deletion of hepatic CTP:phosphocholine cytidylyltransferase α in mice decreases plasma high density and very low density lipoproteins
Targeted deletion of hepatic CTP:phosphocholine cytidylyltransferase α in mice decreases plasma high density and very low density lipoproteins
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DOI：
10.1074/jbc.m404027200
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发表时间：
2004-11-05
影响因子：
4.8
通讯作者：
Vance, DE
中科院分区：
文献类型：
--
作者：
Jacobs, RL;Devlin, C;Vance, DE
CTP: phosphocholine cytidyltransferase （CT）是cdp -胆碱途径中生物合成磷脂酰胆碱的关键调控酶。肝细胞既表达α和β 2亚型的CT，也可以通过磷脂酰乙醇胺n -甲基转移酶催化的磷脂酰乙醇胺序贯甲基化合成磷脂酰胆碱。为了确定CTalpha的功能重要性，我们创建了一只小鼠，通过Cre/LoxP程序特异性灭活肝脏CTalpha基因。在CTalpha敲除小鼠中，肝脏CT活性（由于残余CTbeta2活性和非肝细胞活性）为正常的15%，而磷脂酰乙醇胺n -甲基转移酶活性比对照组提高了2倍。肝脏脂质分析表明，雌性基因敲除小鼠的磷脂酰胆碱水平降低，甘油三酯积累。CTalpha基因敲除组血浆磷脂酰胆碱浓度降低（与性别无关），高密度脂蛋白（胆固醇和载脂蛋白ai）和极低密度脂蛋白（三酰甘油和载脂蛋白ob100）水平也降低。小鼠注射Triton WR1339的实验表明，与对照组相比，肝特异性CTalpha敲除小鼠的apoB分泌减少。这些结果表明，肝CTalpha在调节肝脏和全身脂质和脂蛋白代谢方面具有重要作用。
CTP: phosphocholine cytidylyltransferase (CT) is the key regulatory enzyme in the CDP-choline pathway for the biosynthesis of phosphatidylcholine. Hepatic cells express both an alpha and a beta2 isoform of CT and can also synthesize phosphatidylcholine via the sequential methylation of phosphatidylethanolamine catalyzed by phosphatidylethanolamine N-methyltransferase. To ascertain the functional importance of CTalpha, we created a mouse in which the hepatic CTalpha gene was specifically inactivated by the Cre/LoxP procedure. In CTalpha knockout mice, hepatic CT activity ( due to residual CTbeta2 activity as well as activity in nonhepatic cells) was 15% of normal, whereas phosphatidylethanolamine N-methyltransferase activity was elevated 2-fold compared with controls. Lipid analyses of the liver indicated that female knockout mice had reduced phosphatidylcholine levels and accumulated triacylglycerols. The plasma phosphatidylcholine concentration was reduced in the CTalpha knockout ( independent of gender), as were levels of high density lipoproteins ( cholesterol and apoAI) and very low density lipoproteins ( triacylglycerols and apoB100). Experiments in which mice were injected with Triton WR1339 indicated that apoB secretion was decreased in hepatic-specific CTalpha knockout mice compared with controls. These results suggest an important role for hepatic CTalpha in regulating both hepatic and systemic lipid and lipoprotein metabolism.