Elimination of the CDP-ethanolamine Pathway Disrupts Hepatic Lipid Homeostasis
Elimination of the CDP-ethanolamine Pathway Disrupts Hepatic Lipid Homeostasis
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DOI：
10.1074/jbc.m109.031336
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发表时间：
2009-10-02
影响因子：
4.8
通讯作者：
Jackowski, Suzanne
中科院分区：
文献类型：
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作者：
Leonardi, Roberta;Frank, Matthew W.;Jackowski, Suzanne
磷酸乙醇胺胞酰转移酶（ECT）在合成磷脂酰乙醇胺（PtdEtn）的主要途径中催化速率控制步骤。在小鼠中，肝细胞特异性的ECT基因缺失导致正常动物没有明显的肝损伤或炎症迹象。与对照组相比，ect缺失肝脏中PtdEtn的分子种类发生了显著变化，并且与磷脂酰丝氨酸（PtdSer）池的组成相匹配，说明PtdEtn的合成完全依赖于PtdSer脱羧酶途径。PtdSer结构受PtdSer合成酶底物特异性控制，PtdSer合成酶选择性地将含有硬脂酸酯和多不饱和脂肪酸的磷脂酰胆碱分子种转化为PtdSer。没有证据表明PtdEtn存在脂肪酸重塑。通过cdp -乙醇胺途径消除二酰基甘油的利用，导致三酰基甘油在充斥脂滴的ect缺陷肝细胞中增加10倍。甘油三酯的积累与驱动从头脂肪生成的转录因子和靶基因的表达显著升高有关。内质网中二酰基甘油利用的ECT通路缺失，会引发脂肪酸合成增加，从而支持三酰基甘油的形成，导致肝脏脂肪变性。
Phosphoethanolamine cytidylyltransferase (ECT) catalyzes the rate-controlling step in a major pathway for the synthesis of phosphatidylethanolamine (PtdEtn). Hepatocyte-specific deletion of the ECT gene in mice resulted in normal appearing animals without overt signs of liver injury or inflammation. The molecular species of PtdEtn in the ECT-deficient livers were significantly altered compared with controls and matched the composition of the phosphatidylserine (PtdSer) pool, illustrating the complete reliance on the PtdSer decarboxylase pathway for PtdEtn synthesis. PtdSer structure was controlled by the substrate specificity of PtdSer synthase that selectively converted phosphatidylcholine molecular species containing stearate paired with a polyunsaturated fatty acid to PtdSer. There was no evidence for fatty acid remodeling of PtdEtn. The elimination of diacylglycerol utilization by the CDP-ethanolamine pathway led to a 10-fold increase in triacylglycerols in the ECT-deficient hepatocytes that became engorged with lipid droplets. Triacylglycerol accumulation was associated with a significant elevation in the expression of the transcription factors and target genes that drive de novo lipogenesis. The absence of the ECT pathway for diacylglycerol utilization at the endoplasmic reticulum triggers increased fatty acid synthesis to support the formation of triacylglycerols leading to liver steatosis.