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

Hong Chen, Chong Liu, Qian Wang, Mingrui Xiong, Xia Zeng, Dong Yang, Yunhao Xie, Hua Su, Yu Zhang, Yixue Huang, Yuchen Chen, Junqiu Yue, Chengyu Liu, Shun Wang, Kun Huang () and Ling Zheng ()
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Hong Chen: Huazhong University of Science and Technology
Chong Liu: Wuhan University
Qian Wang: Huazhong University of Science and Technology
Mingrui Xiong: Huazhong University of Science and Technology
Xia Zeng: Huazhong University of Science and Technology
Dong Yang: Huazhong University of Science and Technology
Yunhao Xie: Wuhan University
Hua Su: Huazhong University of Science and Technology
Yu Zhang: Huazhong University of Science and Technology
Yixue Huang: Huazhong University of Science and Technology
Yuchen Chen: Huazhong University of Science and Technology
Junqiu Yue: Huazhong University of Science and Technology
Chengyu Liu: Wuhan Hospital of Traditional and Western Medicine
Shun Wang: Wuhan Hospital of Traditional and Western Medicine
Kun Huang: Huazhong University of Science and Technology
Ling Zheng: Wuhan University

Nature Communications, 2022, vol. 13, issue 1, 1-19

Abstract: Abstract 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 Lys310 and Lys330, 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.

Date: 2022
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DOI: 10.1038/s41467-022-31476-0

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