法尼甾体X受体
内分泌学
内科学
牛磺酸
脂肪变性
G蛋白偶联胆汁酸受体
兴奋剂
脂质代谢
生物
受体
化学
胆汁酸
核受体
医学
生物化学
氨基酸
基因
转录因子
作者
Changtao Jiang,Cen Xie,Ying Lv,Jing Li,Kristopher W. Krausz,Jing-Min Shi,Chad Brocker,Dhimant Desai,Shantu Amin,William H. Bisson,Yulan Liu,Оксана Гаврилова,Andrew D. Patterson,Frank J. Gonzalez
摘要
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.
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