FADD is a key regulator of lipid metabolism

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• 作者：Hongqin Zhuang ; Xueshi Wang ; Daolong Zha ; Ziyi Gan ; Fangfang Cai ; Pan Du ; Yunwen Yang ; Bingya Yang ; Xiangyu Zhang ; Chun Yao ; Yuqiang Zhou ; Chizhou Jiang ; Shengwen Guan ; Xuerui Zhang ; Jing Zhang ; Wenhui Jiang ; Qingang Hu and Zi-Chun Hua
• 刊名：EMBO Molecular Medicine
• 出版年：2016
• 出版时间：August 2016
• 年：2016
• 卷：8
• 期：8
• 页码：895-918
• 全文大小：3562K
• ISSN：1757-4684

文摘

FADD, a classical apoptotic signaling adaptor, was recently reported to have non-apoptotic functions. Here, we report the discovery that FADD regulates lipid metabolism. PPAR-α is a dietary lipid sensor, whose activation results in hypolipidemic effects. We show that FADD interacts with RIP140, which is a corepressor for PPAR-α, and FADD phosphorylation-mimic mutation (FADD-D) or FADD deficiency abolishes RIP140-mediated transcriptional repression, leading to the activation of PPAR-α. FADD-D-mutant mice exhibit significantly decreased adipose tissue mass and triglyceride accumulation. Also, they exhibit increased energy expenditure with enhanced fatty acid oxidation in adipocytes due to the activation of PPAR-α. Similar metabolic phenotypes, such as reduced fat formation, insulin resistance, and resistance to HFD-induced obesity, are shown in adipose-specific FADD knockout mice. Additionally, FADD-D mutation can reverse the severe genetic obesity phenotype of ob/ob mice, with elevated fatty acid oxidation and oxygen consumption in adipose tissue, improved insulin resistance, and decreased triglyceride storage. We conclude that FADD is a master regulator of glucose and fat metabolism with potential applications for treatment of insulin resistance and obesity.