Li Peishan, Song Yu, Zan Wenying, Qin Liping, Han Shuang, Jiang Baichun, Dou Hao, Shao Changshun, Gong Yaoqin
The Key Laboratory of Experimental Teratology, Ministry of Education and Department of Molecular Medicine and Genetics, Shandong University School of Medicine, Jinan, Shandong, People's Republic of China.
The Key Laboratory of Experimental Teratology, Ministry of Education and Department of Molecular Medicine and Genetics, Shandong University School of Medicine, Jinan, Shandong, People's Republic of China
Diabetes. 2017 Feb;66(2):300-313. doi: 10.2337/db16-0743. Epub 2016 Nov 29.
Obesity and obesity-associated diseases are linked to dysregulation of the peroxisome proliferator-activated receptor γ (PPARγ) signaling pathway. Identification of the factors that regulate PPARγ expression and activity is crucial for combating obesity. However, the ubiquitin E3 ligases that target PPARγ for proteasomal degradation have been rarely identified, and their functions in vivo have not been characterized. Here we report that CUL4B-RING E3 ligase (CRL4B) negatively regulates PPARγ by promoting its polyubiquitination and proteasomal degradation. Depletion of CUL4B led to upregulation of PPARγ-regulated genes and facilitated adipogenesis. Adipocyte-specific Cul4b knockout (AKO) mice being fed a high-fat diet exhibited increased body fat accumulation that was mediated by increased adipogenesis. However, AKO mice showed improved metabolic phenotypes, including increased insulin sensitivity and glucose tolerance. Correspondingly, there was a decreased inflammatory response in adipose tissues of AKO mice. Genetic inhibition of CUL4B thus appears to phenocopy the beneficial effects of PPARγ agonists. Collectively, this study establishes a critical role of CRL4B in the regulation of PPARγ stability and insulin sensitivity and suggests that CUL4B could be a potential therapeutic target for combating obesity and metabolic syndromes.
肥胖及肥胖相关疾病与过氧化物酶体增殖物激活受体γ（PPARγ）信号通路失调有关。识别调控PPARγ表达及活性的因子对于对抗肥胖至关重要。然而，靶向PPARγ进行蛋白酶体降解的泛素E3连接酶鲜有被鉴定出来，其在体内的功能也尚未得到表征。在此，我们报告CUL4B-RING E3连接酶（CRL4B）通过促进PPARγ的多聚泛素化及蛋白酶体降解对其进行负调控。CUL4B的缺失导致PPARγ调控基因的上调并促进脂肪生成。喂食高脂饮食的脂肪细胞特异性Cul4b基因敲除（AKO）小鼠表现出因脂肪生成增加介导的体脂积累增加。然而，AKO小鼠表现出改善的代谢表型，包括胰岛素敏感性增加和糖耐量增加。相应地，AKO小鼠脂肪组织中的炎症反应减弱。因此，对CUL4B的基因抑制似乎模拟了PPARγ激动剂的有益作用。总的来说，本研究确立了CRL4B在调控PPARγ稳定性及胰岛素敏感性中的关键作用，并表明CUL4B可能是对抗肥胖和代谢综合征的一个潜在治疗靶点。
