Fenofibrate insulates diacylglycerol in lipid droplet/ER and preserves insulin signaling transduction in the liver of high fat fed mice
Fenofibrate insulates diacylglycerol in lipid droplet/ER and preserves insulin signaling transduction in the liver of high fat fed mice
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DOI：
10.1016/j.bbadis.2015.04.005
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发表时间：
2015-07-01
影响因子：
6.2
通讯作者：
Ye, Ji-Ming
中科院分区：
文献类型：
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作者：
Chan, Stanley M. H.;Zeng, Xiao-Yi;Ye, Ji-Ming
肝脏脂肪变性通常与胰岛素抵抗有关，这是肝脏代谢综合征的一个标志。本研究探讨了非诺贝特(FB)诱导的PPARα激活对高脂饮食(HF)小鼠胰岛素抵抗和肝脏脂肪变性的影响，高脂饮食增加了脂肪流入肝脏。给小鼠喂饲HF饲料，诱导胰岛素抵抗和肝脏脂肪变性。FB激活PPARα，改善HF饮食引起的糖耐量异常和肝脏胰岛素抵抗，但不改变肝脏脂肪变性或炎症信号(INK或IKK)。有趣的是，FB处理同时增加了脂肪酸(FA)的合成(50%)和氧化(66%，均P<；0.01)为中间脂代谢产物，这表明在操作中FA的氧化-合成循环。与这些作用相关的是，二酰甘油(DAGs)被隔离在脂滴/内质网之间，从而减少了它们在细胞膜中的沉积，这是已知的损害胰岛素信号转导的因素。这些发现表明，膜DAG的减少(而不是总的肝脏脂肪变性)可能是非诺贝特诱导的PPARα激活对预防饮食脂肪诱导的肝脏胰岛素抵抗的关键。(C)2015爱思唯尔B.V.保留所有权利。
Hepatic steatosis is often associated with insulin resistance as a hallmark of the metabolic syndrome in the liver. The present study investigated the effects of PPAR alpha activation induced by fenofibrate (FB) on the relationship of insulin resistance and hepatic steatosis in mice fed a high-fat (HF) diet, which increases lipid influx into the liver. Mice were fed HF diet to induce insulin resistance and hepatic steatosis with or without FB. FB activated PPAR alpha and ameliorated HF diet-induced glucose intolerance and hepatic insulin resistance without altering either hepatic steatosis or inflammation signaling (INK or IKK). Interestingly, FB treatment simultaneously increased fatty acid (FA) synthesis (50%) and oxidation (66%, both p < 0.01) into intermediate lipid metabolites, suggesting a FA oxidation-synthesis cycling in operation. Associated with these effects, diacylglycerols (DAGs) were sequestered within the lipid droplet/ER compartment, thus reducing their deposition in the cellular membrane, which is known to impair insulin signal transduction. These findings suggest that the reduction in membrane DAGs (rather than total hepatic steatosis) may be critical for the protection by fenofibrate-induced PPAR alpha activation against hepatic insulin resistance induced by dietary fat. (C) 2015 Elsevier B.V. All rights reserved.