Consequences of lipid droplet coat protein downregulation in liver cells: abnormal lipid droplet metabolism and induction of insulin resistance.
Consequences of lipid droplet coat protein downregulation in liver cells: abnormal lipid droplet metabolism and induction of insulin resistance.
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DOI：
10.2337/db07-1383
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发表时间：
2008-08
期刊：
影响因子：
7.7
通讯作者：
Sztalryd, Carole
中科院分区：
文献类型：
--
作者：
Bell, Ming;Wang, Hong;Chen, Hui;McLenithan, John C.;Gong, Da-Wei;Yang, Rong-Zee;Yu, Daozhan;Fried, Susan K.;Quon, Michael J.;Londos, Constantine;Sztalryd, Carole
目的：细胞内脂滴(LDS)在非脂肪组织中的蓄积被认为是肥胖患者发生胰岛素抵抗的一个强有力的预后因素。脂蛋白被Perilipin、脂肪分化相关蛋白、尾部相互作用蛋白等47kd(PAT)蛋白包裹，这些蛋白被认为通过调节脂解来调节LD的周转。我们的假设是，PAT蛋白调节LD新陈代谢，从而调节胰岛素抵抗。研究设计和方法-我们使用细胞培养模型(负载油酸的小鼠AML12)和小干扰RNA直接评估PAT蛋白对LD积累、脂代谢和胰岛素作用的影响。还检测了与饮食诱导肥胖(DIO)小鼠肝脏中沉积的过量脂肪相关的PAT蛋白。结果：缺乏PAT蛋白的细胞显示出LD大小的显著增加和LD数量的减少。此外，随着LD表面脂肪甘油三酯脂肪酶(∼)的增加，脂解率增加了2-2.5%。PAT蛋白的下调也会产生胰岛素抵抗，表现为胰岛素对Akt磷酸化的刺激减少(P<；0.001)。肌醇磷脂依赖的激酶-1和肌醇磷脂3-激酶减少，胰岛素受体底物-1 307磷酸化增加。DIO小鼠肝脏中的脂质增加伴随着PAT组成的变化，但也增加了ATGL，这表明相对的PAT缺乏。结论：这些数据确立了PAT蛋白作为LD表面的表面活性物质的重要作用，将脂肪包装在较小的单位中，并限制脂肪酶的访问，从而防止胰岛素抵抗。我们认为，与异位脂肪量相关的PAT蛋白缺乏可能导致肥胖和2型糖尿病的细胞功能障碍。
OBJECTIVE—Accumulation of intracellular lipid droplets (LDs) in non-adipose tissues is recognized as a strong prognostic factor for the development of insulin resistance in obesity. LDs are coated with perilipin, adipose differentiation–related protein, tail interacting protein of 47 kd (PAT) proteins that are thought to regulate LD turnover by modulating lipolysis. Our hypothesis is that PAT proteins modulate LD metabolism and therefore insulin resistance. RESEARCH DESIGN AND METHODS—We used a cell culture model (murine AML12 loaded with oleic acid) and small interfering RNA to directly assess the impact of PAT proteins on LD accumulation, lipid metabolism, and insulin action. PAT proteins associated with excess fat deposited in livers of diet-induced obese (DIO) mice were also measured. RESULTS—Cells lacking PAT proteins exhibited a dramatic increase in LD size and a decrease in LD number. Further, the lipolytic rate increased by ∼2- to 2.5-fold in association with increased adipose triglyceride lipase (ATGL) at the LD surface. Downregulation of PAT proteins also produced insulin resistance, as indicated by decreased insulin stimulation of Akt phosphorylation (P < 0.001). Phosphoinositide-dependent kinase-1 and phosphoinositide 3-kinase decreased, and insulin receptor substrate-1 307 phosphorylation increased. Increased lipids in DIO mice livers were accompanied by changes in PAT composition but also increased ATGL, suggesting a relative PAT deficiency. CONCLUSIONS—These data establish an important role for PAT proteins as surfactant at the LD surface, packaging lipids in smaller units and restricting access of lipases and thus preventing insulin resistance. We suggest that a deficiency of PAT proteins relative to the quantity of ectopic fat could contribute to cellular dysfunction in obesity and type 2 diabetes.
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影响因子：
9.8
作者：
Lefevre, C;Jobard, F;Fischer, J
通讯作者：
Fischer, J
影响因子：
2.5
作者：
Lu, XY;Gruia-Gray, J;Kimmel, AR
通讯作者：
Kimmel, AR
影响因子：
7.7
作者：
Kershaw, EE;Hamm, JK;Flier, JS
通讯作者：
Flier, JS
影响因子：
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作者：
Gao, ZG;Zhang, XY;Ye, JP
通讯作者：
Ye, JP
影响因子：
56.9
作者：
Haemmerle, G;Lass, A;Zechner, R
通讯作者：
Zechner, R