生物
葡萄糖稳态
脂质代谢
泛素
胰岛素抵抗
磷酸化
内分泌学
脱氮酶
过氧化物酶体增殖物激活受体
核受体
内科学
受体
细胞生物学
转录因子
生物化学
胰岛素
基因
医学
作者
Na Zhou,Hailong Qi,Junjun Liu,Guangze Zhang,Jianping Liu,Ning Liu,Minglu Zhu,Xuyang Zhao,Chang Ho Song,Zhe Zhou,Jingjing Gong,Ridong Li,Xinyu Bai,Yan Jin,Yongfeng Song,Yuxin Yin
出处
期刊:Cell Metabolism
[Elsevier]
日期:2022-06-07
卷期号:34 (7): 1023-1041.e8
被引量:22
标识
DOI:10.1016/j.cmet.2022.05.005
摘要
The ovarian-tumor-domain-containing deubiquitinases (OTUDs) block ubiquitin-dependent protein degradation and are involved in diverse signaling pathways. We discovered a rare OTUD3 c.863G>A mutation in a family with an early age of onset of diabetes. This mutation reduces the stability and catalytic activity of OTUD3. We next constructed an experiment with Otud3−/− mice and found that they developed worse obesity, dyslipidemia, and insulin resistance than wild-type mice when challenged with a high-fat diet (HFD). We further found that glucose and fatty acids stimulate CREB-binding-protein-dependent OTUD3 acetylation, promoting its nuclear translocation, where OTUD3 regulates various genes involved in glucose and lipid metabolism and oxidative phosphorylation by stabilizing peroxisome-proliferator-activated receptor delta (PPARδ). Moreover, targeting PPARδ using a specific agonist can partially rescue the phenotype of HFD-fed Otud3−/− mice. We propose that OTUD3 is an important regulator of energy metabolism and that the OTUD3 c.863G>A is associated with obesity and a higher risk of diabetes.
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