Dual regulation of adipose triglyceride lipase by pigment epithelium-derived factor: A novel mechanistic insight into progressive obesity
Dual regulation of adipose triglyceride lipase by pigment epithelium-derived factor: A novel mechanistic insight into progressive obesity
复制标题
色素上皮衍生因子对脂肪甘油三酯脂肪酶的双重调节：对进行性肥胖的新机制见解
DOI：
10.1016/j.mce.2013.07.001
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发表时间：
2013-09-05
影响因子：
4.1
通讯作者：
Cai, Weibin
中科院分区：
文献类型：
--
作者：
Dai, Zhiyu;Qi, Weiwei;Cai, Weibin
血浆游离脂肪酸（FFA）的升高和脂肪组织中甘油三酯的积累在肥胖和胰岛素抵抗的过程中被观察到。这一矛盾现象及其潜在机制尚未得到彻底阐明。最近的研究表明，色素上皮衍生因子（PEDF）通过激活脂肪甘油三酯脂肪酶（ATGL）导致肥胖小鼠血浆FFA升高和胰岛素抵抗。然而，我们发现尽管PEDF促进脂肪分解，但却下调了脂肪ATGL蛋白的表达。血浆PEDF和FFA的增加与进行性高脂肪饮食有关，这些结果还伴随着脂肪积累和脂肪ATGL的减少。外源性PEDF注射使肥胖小鼠脂肪ATGL蛋白表达下调，血浆FFA升高，而内源性PEDF中和可显著挽救肥胖小鼠脂肪ATGL的减少，并降低血浆FFA。PEDF在分化的3T3-L1细胞中以时间和剂量依赖的方式降低ATGL蛋白的表达。小干扰rna介导的PEDF敲低和抗体介导的PEDF阻断增加内源性ATGL表达，PEDF过表达下调ATGL。PEDF降低了ATGL的半衰期，并通过泛素依赖的蛋白酶体降解途径调节ATGL的降解。PEDF通过ATGL抑制剂溴烯醇内酯刺激ATGL的脂解，PEDF还下调G0/G1开关基因2 （G0S2）的表达，G0S2是ATGL激活的内源性抑制剂。总的来说，PEDF通过蛋白酶体介导的脂肪细胞降解来减弱ATGL蛋白的积累，PEDF还通过激活ATGL来促进脂肪分解。PEDF升高可能通过其对ATGL的双重调节导致进行性肥胖和胰岛素抵抗。2013爱思唯尔爱尔兰有限公司版权所有。
Both elevated plasma free fatty acids (FFA) and accumulating triglyceride in adipose tissue are observed in the process of obesity and insulin resistance. This contradictory phenomenon and its underlying mechanisms have not been thoroughly elucidated. Recent studies have demonstrated that pigment epithelium-derived factor (PEDF) contributes to elevated plasma FFA and insulin resistance in obese mice via the activation of adipose triglyceride lipase (ATGL). However, we found that PEDF downregulated adipose ATGL protein expression despite of enhancing lipolysis. Plasma PEDF and FFA were increased in associated with a progressive high-fat-diet, and those outcomes were also accompanied by fat accumulation and a reduction in adipose ATGL. Exogenous PEDF injection downregulated adipose ATGL protein expression and elevated plasma FFA, while endogenous PEDF neutralization significantly rescued the adipose ATGL reduction and also reduced plasma FFA in obese mice. PEDF reduced ATGL protein expression in a time- and dose-dependent manner in differentiated 3T3-L1 cells. Small interfering RNA-mediated PEDF knockdown and antibody-mediated PEDF blockage increased endogenous ATGL expression, and PEDF overexpression downregulated ATGL. PEDF resulted in a decreased half-life of ATGL and regulated ATGL degradation via ubiquitin-dependent proteasomal degradation pathway. PEDF stimulated lipolysis via ATGL using ATGL inhibitor bromoenol lactone, and PEDF also downregulated G0/G1 switch gene 2 (G0S2) expression, which is an endogenous inhibitor of ATGL activation. Overall, PEDF attenuated ATGL protein accumulation via proteasome-mediated degradation in adipocytes, and PEDF also promoted lipolysis by activating ATGL. Elevated PEDF may contribute to progressive obesity and insulin resistance via its dual regulation of ATGL. (c) 2013 Elsevier Ireland Ltd. All rights reserved.