B3galt5 functions as a PXR target gene and regulates obesity and insulin resistance by maintaining intestinal integrity

Jinhang Zhang, Ya Huang, Hong Li, Pengfei Xu, Qinhui Liu, Yang Sun, Zijing Zhang, Tong Wu, Qin Tang, Qingyi Jia, Yan Xia, Ying Xu, Xiandan Jing, Jiahui Li, Li Mo, Wen Xie, Aijuan Qu, Jinhan He () and Yanping Li ()
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Jinhang Zhang: Institute of Metabolic Diseases and Pharmacotherapy, National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University
Ya Huang: Institute of Metabolic Diseases and Pharmacotherapy, National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University
Hong Li: Institute of Metabolic Diseases and Pharmacotherapy, National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University
Pengfei Xu: University of Pittsburgh
Qinhui Liu: Institute of Metabolic Diseases and Pharmacotherapy, National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University
Yang Sun: The First Affiliated Hospital of Kunming Medical University, Yunnan Institute of Digestive Disease
Zijing Zhang: Institute of Metabolic Diseases and Pharmacotherapy, National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University
Tong Wu: Institute of Metabolic Diseases and Pharmacotherapy, National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University
Qin Tang: Institute of Metabolic Diseases and Pharmacotherapy, National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University
Qingyi Jia: Institute of Metabolic Diseases and Pharmacotherapy, National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University
Yan Xia: Institute of Metabolic Diseases and Pharmacotherapy, National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University
Ying Xu: Institute of Metabolic Diseases and Pharmacotherapy, National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University
Xiandan Jing: Institute of Metabolic Diseases and Pharmacotherapy, National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University
Jiahui Li: Institute of Metabolic Diseases and Pharmacotherapy, National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University
Li Mo: West China Hospital of Sichuan University
Wen Xie: University of Pittsburgh
Aijuan Qu: School of Basic Medical Sciences, Capital Medical University
Jinhan He: Institute of Metabolic Diseases and Pharmacotherapy, National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University
Yanping Li: Institute of Metabolic Diseases and Pharmacotherapy, National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University

Nature Communications, 2024, vol. 15, issue 1, 1-16

Abstract: Abstract Pregnane X receptor (PXR) has been reported to regulate glycolipid metabolism. The dysfunction of intestinal barrier contributes to metabolic disorders. However, the role of intestinal PXR in metabolic diseases remains largely unknown. Here, we show that activation of PXR by tributyl citrate (TBC), an intestinal-selective PXR agonist, improves high fat diet (HFD)-induced obesity. The metabolic benefit of intestinal PXR activation is associated with upregulation of β-1,3 galactosyltransferase 5 (B3galt5). Our results reveal that B3galt5 mainly expresses in the intestine and is a direct PXR transcriptional target. B3galt5 knockout exacerbates HFD-induced obesity, insulin resistance and inflammation. Mechanistically, B3galt5 is essential to maintain the integrity of intestinal mucus barrier. B3galt5 ablation impairs the O-glycosylation of mucin2, destabilizes the mucus layer, and increases intestinal permeability. Furthermore, B3galt5 deficiency abolishes the beneficial effect of intestinal PXR activation on metabolic disorders. Our results suggest the intestinal-selective PXR activation regulates B3galt5 expression and maintains metabolic homeostasis, making it a potential therapeutic strategy in obesity.

Date: 2024
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DOI: 10.1038/s41467-024-50198-z

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