Pathak Preeti, Liu Hailiang, Boehme Shannon, Xie Cen, Krausz Kristopher W, Gonzalez Frank, Chiang John Y L
From the Department of Integrative Medical Sciences, College of Medicine, Northeast Ohio Medical University, Rootstown, Ohio 44272 and.
the Laboratory of Metabolism, Center for Cancer Research, NCI, National Institutes of Health, Bethesda, Maryland 20892.
J Biol Chem. 2017 Jun 30;292(26):11055-11069. doi: 10.1074/jbc.M117.784322. Epub 2017 May 6.
The bile acid-activated receptors, nuclear farnesoid X receptor (FXR) and the membrane Takeda G-protein receptor 5 (TGR5), are known to improve glucose and insulin sensitivity in obese and diabetic mice. However, the metabolic roles of these two receptors and the underlying mechanisms are incompletely understood. Here, we studied the effects of the dual FXR and TGR5 agonist INT-767 on hepatic bile acid synthesis and intestinal secretion of glucagon-like peptide-1 (GLP-1) in wild-type, , and mice. INT-767 efficaciously stimulated intracellular Ca levels, cAMP activity, and GLP-1 secretion and improved glucose and lipid metabolism more than did the FXR-selective obeticholic acid and TGR5-selective INT-777 agonists. Interestingly, INT-767 reduced expression of the genes in the classic bile acid synthesis pathway but induced those in the alternative pathway, which is consistent with decreased taurocholic acid and increased tauromuricholic acids in bile. Furthermore, FXR activation induced expression of FXR target genes, including fibroblast growth factor 15, and unexpectedly and prohormone convertase 1/3 gene expression in the ileum. We identified an FXR-responsive element on the gene promoter. and mice exhibited reduced GLP-1 secretion, which was stimulated by INT-767 in the mice but not in the mice. Our findings uncovered a novel mechanism in which INT-767 activation of FXR induces gene expression and increases Ca levels and cAMP activity to stimulate GLP-1 secretion and improve hepatic glucose and lipid metabolism in high-fat diet-induced obese mice. Activation of both FXR and TGR5 may therefore represent an effective therapy for managing hepatic steatosis, obesity, and diabetes.
胆汁酸激活受体，即核法尼醇X受体（FXR）和膜型武田G蛋白受体5（TGR5），已知可改善肥胖和糖尿病小鼠的血糖及胰岛素敏感性。然而，这两种受体的代谢作用及其潜在机制尚未完全明确。在此，我们研究了双FXR和TGR5激动剂INT-767对野生型、 及 小鼠肝脏胆汁酸合成和胰高血糖素样肽-1（GLP-1）肠道分泌的影响。与FXR选择性激动剂奥贝胆酸和TGR5选择性激动剂INT-777相比，INT-767更有效地刺激细胞内钙离子水平、环磷酸腺苷（cAMP）活性及GLP-1分泌，并改善葡萄糖和脂质代谢。有趣的是，INT-767降低了经典胆汁酸合成途径中基因的表达，但诱导了替代途径中基因的表达，这与胆汁中牛磺胆酸减少和牛磺鹅去氧胆酸增加一致。此外，FXR激活诱导了FXR靶基因的表达，包括成纤维细胞生长因子15，并且意外地诱导了回肠中 及激素原转化酶1/3基因的表达。我们在 基因启动子上鉴定出一个FXR反应元件。 及 小鼠表现出GLP-1分泌减少，INT-767可刺激 小鼠的GLP-1分泌，但对 小鼠无此作用。我们的研究结果揭示了一种新机制，即INT-767激活FXR诱导 基因表达并增加钙离子水平和cAMP活性，以刺激GLP-1分泌并改善高脂饮食诱导的肥胖小鼠的肝脏葡萄糖和脂质代谢。因此，同时激活FXR和TGR5可能是治疗肝脂肪变性、肥胖症和糖尿病的有效疗法。
