Intestine-selective farnesoid X receptor inhibition improves obesity-related metabolic dysfunction.
Intestine-selective farnesoid X receptor inhibition improves obesity-related metabolic dysfunction.
复制标题
肠道选择性法尼醇 X 受体抑制可改善肥胖相关的代谢功能障碍。
DOI：
10.1038/ncomms10166
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发表时间：
2015-12-15
影响因子：
16.6
通讯作者：
Gonzalez FJ
中科院分区：
文献类型：
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作者：
Jiang C;Xie C;Lv Y;Li J;Krausz KW;Shi J;Brocker CN;Desai D;Amin SG;Bisson WH;Liu Y;Gavrilova O;Patterson AD;Gonzalez FJ
farnesoid X受体（FXR）调节胆汁酸、脂质和葡萄糖代谢。本研究表明，用甘氨酸-β-胆酸（Gly-MCA）治疗小鼠可抑制肠道内的FXR信号，并改善肥胖小鼠模型的代谢参数。Gly-MCA是一种选择性高亲和力FXR抑制剂，可口服，可预防或逆转小鼠高脂肪饮食诱导和遗传性肥胖、胰岛素抵抗和肝脂肪变性。高亲和力的FXR激动剂GW4064阻断Gly-MCA在肠道中的作用，肠道特异性FXR缺失小鼠对Gly-MCA的有益作用无反应。从机制上讲，Gly-MCA的代谢改善依赖于减少肠源性神经酰胺的生物合成，这直接损害了米色脂肪的产热功能。因此，神经酰胺治疗逆转了高脂肪饮食诱导的肥胖小鼠中Gly-MCA的作用。我们进一步表明，人类回肠活检中的FXR信号与体重指数呈正相关。这些数据表明Gly-MCA可能是治疗代谢性疾病的候选药物。核法内甾体X受体（FXR）被胆汁酸激活并影响能量代谢。在这里，作者报告了一种FXR的小分子抑制剂甘氨酸-ß-胆酸，它可以抑制肠道中的FXR，并通过抑制肠道神经酰胺合成来改善代谢稳态。
The farnesoid X receptor (FXR) regulates bile acid, lipid and glucose metabolism. Here we show that treatment of mice with glycine-β-muricholic acid (Gly-MCA) inhibits FXR signalling exclusively in intestine, and improves metabolic parameters in mouse models of obesity. Gly-MCA is a selective high-affinity FXR inhibitor that can be administered orally and prevents, or reverses, high-fat diet-induced and genetic obesity, insulin resistance and hepatic steatosis in mice. The high-affinity FXR agonist GW4064 blocks Gly-MCA action in the gut, and intestine-specific Fxr-null mice are unresponsive to the beneficial effects of Gly-MCA. Mechanistically, the metabolic improvements with Gly-MCA depend on reduced biosynthesis of intestinal-derived ceramides, which directly compromise beige fat thermogenic function. Consequently, ceramide treatment reverses the action of Gly-MCA in high-fat diet-induced obese mice. We further show that FXR signalling in ileum biopsies of humans positively correlates with body mass index. These data suggest that Gly-MCA may be a candidate for the treatment of metabolic disorders. The nuclear farnesoid X receptor (FXR) is activated by bile acids and influences energy metabolism. Here, the authors report a small molecule inhibitor of FXR, glycine-ß-muricholic acid, which inhibits FXR in the intestine and improves metabolic homeostasis by repressing intestinal ceramide synthesis.