PDF(Pubmed)
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：
已经报道孕烷X受体(PXR)调节糖脂代谢。肠屏障的功能紊乱导致代谢紊乱。然而,肠道PXR在代谢性疾病中的作用尚不清楚。这里,我们显示柠檬酸三丁酯（TBC）对PXR的活化，一种肠道选择性PXR激动剂，改善高脂饮食（HFD）诱导的肥胖。肠PXR活化的代谢益处与β-1,3半乳糖基转移酶5(B3galt5)的上调相关。我们的结果表明，B3galt5主要在肠道中表达，并且是直接的PXR转录靶标。B3galt5敲除会加剧HFD诱导的肥胖，胰岛素抵抗和炎症。机械上,B3galt5对于维持肠粘液屏障的完整性至关重要。B3galt5消融损害粘蛋白2的O-糖基化，使粘液层不稳定，并增加肠道通透性。此外，B3galt5缺乏消除了肠道PXR活化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表达并维持代谢稳态，使其成为肥胖的潜在治疗策略。
