Renal UTX-PHGDH-serine axis regulates metabolic disorders in the kidney and liver

• Published in: Nature communications Vol. 13; no. 1; pp. 3835 - 19
• Main Authors: Chen, Hong, Liu, Chong, Wang, Qian, Xiong, Mingrui, Zeng, Xia, Yang, Dong, Xie, Yunhao, Su, Hua, Zhang, Yu, Huang, Yixue, Chen, Yuchen, Yue, Junqiu, Liu, Chengyu, Wang, Shun, Huang, Kun, Zheng, Ling
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 04.07.2022; Nature Publishing Group; Nature Portfolio
• Subjects: 13/1; 13/109; 13/89; 631/443; 64/60; 692/4022; Dehydrogenase; Dehydrogenases; Diabetes mellitus; Diet; Fatty liver; High fat diet; Histones; Homeostasis; Humanities and Social Sciences; Kidney diseases; Kidneys; Lipid metabolism; Lipids; Liver; Liver diseases; Metabolic disorders; multidisciplinary; Nutrition; Obesity; Oral administration; Overnutrition; Phosphoglycerate dehydrogenase; Renal function; Science; Science (multidisciplinary); Serine; Ubiquitin-protein ligase
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-022-31476-0

Global obesity epidemics impacts human health and causes obesity-related illnesses, including the obesity-related kidney and liver diseases. UTX, a histone H3K27 demethylase, plays important roles in development and differentiation. Here we show that kidney-specific knockout Utx inhibits high-fat diet induced lipid accumulation in the kidney and liver via upregulating circulating serine levels. Mechanistically, UTX recruits E3 ligase RNF114 to ubiquitinate phosphoglycerate dehydrogenase, the rate limiting enzyme for de novo serine synthesis, at Lys 310 and Lys 330 , which leads to its degradation, and thus suppresses renal and circulating serine levels. Consistently, phosphoglycerate dehydrogenase and serine levels are markedly downregulated in human subjects with diabetic kidney disease or obesity-related renal dysfunction. Notably, oral administration of serine ameliorates high-fat diet induced fatty liver and renal dysfunction, suggesting a potential approach against obesity related metabolic disorders. Together, our results reveal a metabolic homeostasis regulation mediated by a renal UTX-PHGDH-serine axis. Chen et al. report on a renal UTX-phosphoglycerate dehydrogenase axis that regulates serine secretion to affect lipid metabolism in the kidney and liver upon over-nutrition, suggesting potential treatment targets for obesity-related diseases.