The soluble epoxide hydrolase determines cholesterol homeostasis by regulating AMPK and SREBP activity
The soluble epoxide hydrolase determines cholesterol homeostasis by regulating AMPK and SREBP activity
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DOI：
10.1016/j.prostaglandins.2016.05.003
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发表时间：
2016-09-01
影响因子：
2.9
通讯作者：
Fleming, Ingrid
中科院分区：
文献类型：
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作者：
Mangels, Nicole;Awwad, Khader;Fleming, Ingrid
可溶性环氧化物水解酶（SEE）的抑制或缺失与降低胆固醇和预防动脉粥样硬化有关。本研究着手鉴定在来自sEH（-/-）小鼠的肝脏中改变的sEH底物或产物，所述sEH底物或产物有助于。在肝脏和分离的肝细胞中，sEH的缺失降低了HMG CoA还原酶、脂肪酸合成酶和低密度脂蛋白受体的表达。固醇调节元件结合蛋白（SREBP）调节所有三种酶的表达，并且在不存在sEH的情况下SREBP活化减弱。这种作用归因于AMPK活化蛋白激酶（AMPK），其在不存在sEH的情况下被激活。野生型与sEH（-/-）同窝仔的肝脏含有显著更高水平的sEH底物12，13-环氧十八碳烯酸，其引起AMPK活化，而相应的sEH产物无活性。因此，AMPK激活和随后的SREBP抑制可以解释sEH（-/-）小鼠脂质代谢酶表达的改变。(C)2016由Elsevier Inc.出版
Inhibition or deletion of the soluble epoxide hydrolase (SEE) has been linked to reduced cholesterol and protection against atherosclerosis. This study set out to identify sEH substrate(s) or product(s), altered in livers from sEH(-/-) mice that contribute to. these beneficial effects.In livers and isolated hepatocytes, deletion of sEH decreased expression of HMG CoA reductase, fatty acid synthase and low density lipoprotein receptor. Sterol regulatory element binding proteins (SREBPs) regulate the expression of all three enzymes and SREBP activation was attenuated in the absence of sEH. The effect was attributed to the AMPK-activated protein kinase (AMPK) which was activated in the absence of sEH. Livers from wild-type versus sEH(-/-) littermates contained significantly higher levels of the sEH substrate 12,13-epoxyoctadecenoic acid, which elicited AMPK activation, while the corresponding sEH product was inactive. Thus, AMPK activation and subsequent inhibition of SREBP can account for the altered expression of lipid metabolizing enzymes in sEH(-/-) mice. (C) 2016 Published by Elsevier Inc.