Puri Vishwajeet, Ranjit Srijana, Konda Silvana, Nicoloro Sarah M C, Straubhaar Juerg, Chawla Anil, Chouinard My, Lin Chenyi, Burkart Alison, Corvera Silvia, Perugini Richard A, Czech Michael P
Program in Molecular Medicine, University of Massachusetts Medical School, 373 Plantation Street, Worcester, MA 01605, USA.
Proc Natl Acad Sci U S A. 2008 Jun 3;105(22):7833-8. doi: 10.1073/pnas.0802063105. Epub 2008 May 28.
Storage of energy as triglyceride in large adipose-specific lipid droplets is a fundamental need in all mammals. Efficient sequestration of fat in adipocytes also prevents fatty acid overload in skeletal muscle and liver, which can impair insulin signaling. Here we report that the Cide domain-containing protein Cidea, previously thought to be a mitochondrial protein, colocalizes around lipid droplets with perilipin, a regulator of lipolysis. Cidea-GFP greatly enhances lipid droplet size when ectopically expressed in preadipocytes or COS cells. These results explain previous findings showing that depletion of Cidea with RNAi markedly elevates lipolysis in human adipocytes. Like perilipin, Cidea and the related lipid droplet protein Cidec/FSP27 are controlled by peroxisome proliferator-activated receptor gamma (PPARgamma). Treatment of lean or obese mice with the PPARgamma agonist rosiglitazone markedly up-regulates Cidea expression in white adipose tissue (WAT), increasing lipid deposition. Strikingly, in both omental and s.c. WAT from BMI-matched obese humans, expression of Cidea, Cidec/FSP27, and perilipin correlates positively with insulin sensitivity (HOMA-IR index). Thus, Cidea and other lipid droplet proteins define a novel, highly regulated pathway of triglyceride deposition in human WAT. The data support a model whereby failure of this pathway results in ectopic lipid accumulation, insulin resistance, and its associated comorbidities in humans.
在所有哺乳动物中，将能量以甘油三酯的形式储存于大型脂肪特异性脂滴中是一项基本需求。脂肪细胞中高效的脂肪隔离还可防止骨骼肌和肝脏中脂肪酸过载，否则可能会损害胰岛素信号传导。在此我们报告，之前被认为是线粒体蛋白的含Cide结构域蛋白Cidea，与脂解调节因子围脂滴蛋白共定位于脂滴周围。当在脂肪前体细胞或COS细胞中异位表达时，Cidea-GFP可显著增大脂滴大小。这些结果解释了之前的研究发现，即RNA干扰使Cidea缺失会显著提高人类脂肪细胞中的脂解作用。与围脂滴蛋白一样，Cidea及相关脂滴蛋白Cidec/FSP27受过氧化物酶体增殖物激活受体γ（PPARγ）调控。用PPARγ激动剂罗格列酮处理瘦小鼠或肥胖小鼠，可显著上调白色脂肪组织（WAT）中Cidea的表达，增加脂质沉积。引人注目的是，在体重指数匹配的肥胖人类的网膜和皮下WAT中，Cidea、Cidec/FSP27和围脂滴蛋白的表达均与胰岛素敏感性（HOMA-IR指数）呈正相关。因此，Cidea和其他脂滴蛋白定义了人类WAT中一条新的、高度受调控的甘油三酯沉积途径。这些数据支持了一种模型，即该途径的缺陷会导致人类异位脂质蓄积、胰岛素抵抗及其相关合并症。
