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B3galt5 作为 PXR 靶基因，通过维持肠道完整性来调节肥胖和胰岛素抵抗。

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

机构信息

Department of Pharmacy, Institute of Metabolic Diseases and Pharmacotherapy, National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, Chengdu, Sichuan Province, China.

Department of Pharmacy, GuiQian International General Hospital, Guiyang, China.

出版信息

Nat Commun. 2024 Jul 14;15(1):5919. doi: 10.1038/s41467-024-50198-z.

DOI:10.1038/s41467-024-50198-z
PMID:39004626
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC11247088/
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.

摘要

妊娠相关 X 受体 (PXR) 已被报道可调节糖脂代谢。肠道屏障功能障碍与代谢紊乱有关。然而，肠道 PXR 在代谢性疾病中的作用在很大程度上仍不清楚。在这里，我们发现三丁基柠檬酸 (TBC) 激活 PXR，一种肠道选择性 PXR 激动剂，可改善高脂肪饮食 (HFD) 诱导的肥胖。肠道 PXR 激活的代谢益处与β-1,3 半乳糖基转移酶 5 (B3galt5) 的上调有关。我们的结果表明，B3galt5 主要在肠道中表达，是 PXR 的直接转录靶标。B3galt5 敲除加剧 HFD 诱导的肥胖、胰岛素抵抗和炎症。在机制上，B3galt5 对于维持肠道黏液屏障的完整性是必需的。B3galt5 的缺失会破坏粘蛋白 2 的 O-糖基化，使黏液层不稳定，并增加肠道通透性。此外，B3galt5 缺失消除了肠道 PXR 激活对代谢紊乱的有益作用。我们的结果表明，肠道选择性 PXR 激活调节 B3galt5 的表达并维持代谢稳态，使其成为肥胖症的一种潜在治疗策略。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8f0d/11247088/736f7484088f/41467_2024_50198_Fig8_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8f0d/11247088/7fa8710a6998/41467_2024_50198_Fig1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8f0d/11247088/42e5485e8d06/41467_2024_50198_Fig2_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8f0d/11247088/38a36ea68a70/41467_2024_50198_Fig3_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8f0d/11247088/7e704adfc5ae/41467_2024_50198_Fig4_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8f0d/11247088/bbf5d64df483/41467_2024_50198_Fig5_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8f0d/11247088/ff0cea23d4b9/41467_2024_50198_Fig6_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8f0d/11247088/749bb2ff695c/41467_2024_50198_Fig7_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8f0d/11247088/736f7484088f/41467_2024_50198_Fig8_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8f0d/11247088/7fa8710a6998/41467_2024_50198_Fig1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8f0d/11247088/42e5485e8d06/41467_2024_50198_Fig2_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8f0d/11247088/38a36ea68a70/41467_2024_50198_Fig3_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8f0d/11247088/7e704adfc5ae/41467_2024_50198_Fig4_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8f0d/11247088/bbf5d64df483/41467_2024_50198_Fig5_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8f0d/11247088/ff0cea23d4b9/41467_2024_50198_Fig6_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8f0d/11247088/749bb2ff695c/41467_2024_50198_Fig7_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8f0d/11247088/736f7484088f/41467_2024_50198_Fig8_HTML.jpg

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