Schittenhelm Björn, Wagner Rebecca, Kähny Verena, Peter Andreas, Krippeit-Drews Peter, Düfer Martina, Drews Gisela
Institute of Pharmacy (B.S., R.W., V.K., P.K.-D., G.D.), Department of Pharmacology, University of Tübingen and Medical Clinic IV (A.P.), D-72076 Tübingen, Germany; and Institute of Pharmaceutical and Medical Chemistry (M.D.), Department of Pharmacology, D-48149 Münster, Germany.
Endocrinology. 2015 Apr;156(4):1263-71. doi: 10.1210/en.2014-1751. Epub 2015 Jan 19.
We have recently shown that the bile acid (BA) taurochenodeoxycholate (TCDC) acutely stimulates insulin secretion via activation of the farnesoid X receptor (FXR). Aims of the current investigation were to discriminate between nongenomic (≤1 h) and genomic effects (24-48 h) of BAs on β-cells and to evaluate whether FXR can modulate the adverse effects of a high-fat diet (HFD). TCDC (500 nM) as well as glycine-conjugated and unconjugated CDC (chenodeoxycholate) increased insulin secretion in acute incubations but did not evoke additional effects after 1-2 days of preincubation. The BAs did not stimulate β-cells of FXR-knockout (KO) mice and activation of the G protein-coupled BA receptor TGR5 was ineffective, suggesting that FXR is the sole BA receptor in β-cells activated by TCDC and its analogues. As opposed to lean mice, obese FXR-KO mice did not show HFD-induced glucose intolerance and increased fasting glucose. The beneficial impact of FXR-KO on glucose metabolism cannot be explained by an adaptive compensation of insulin secretion or β-cell mass. Interestingly, in contrast to its effect on islets from lean mice, the FXR agonist GW4064 was ineffective in stimulating insulin secretion of islets from wild type mice fed a HFD or isolated islets kept in a glucolipotoxic medium. Additional feeding of CDC restored the effect of GW4064. CDC prevented HFD-induced impairment of glucose tolerance and in vitro effects of glucolipotoxicity. The data show that the FXR is the most important BA receptor in β-cells and that FXR signaling in β-cells is impaired by overnutrition, which alters activatability of the FXR.
我们最近发现，胆汁酸（BA）牛磺鹅去氧胆酸（TCDC）可通过激活法尼醇X受体（FXR）来急性刺激胰岛素分泌。本研究的目的是区分BA对β细胞的非基因组效应（≤1小时）和基因组效应（24 - 48小时），并评估FXR是否能调节高脂饮食（HFD）的不良影响。在急性孵育中，TCDC（500 nM）以及甘氨酸结合型和非结合型CDC（鹅去氧胆酸）可增加胰岛素分泌，但预孵育1 - 2天后未产生额外影响。这些胆汁酸不会刺激FXR基因敲除（KO）小鼠的β细胞，且G蛋白偶联胆汁酸受体TGR5的激活无效，这表明FXR是TCDC及其类似物激活的β细胞中唯一的胆汁酸受体。与瘦小鼠不同，肥胖的FXR - KO小鼠未表现出HFD诱导的葡萄糖不耐受和空腹血糖升高。FXR - KO对葡萄糖代谢的有益影响不能通过胰岛素分泌或β细胞量的适应性补偿来解释。有趣的是，与对瘦小鼠胰岛的作用相反，FXR激动剂GW4064对喂食HFD的野生型小鼠的胰岛或置于糖脂毒性培养基中的分离胰岛刺激胰岛素分泌无效。额外喂食CDC可恢复GW4064的作用。CDC可预防HFD诱导的葡萄糖耐量损害以及糖脂毒性的体外效应。数据表明，FXR是β细胞中最重要的胆汁酸受体，且β细胞中的FXR信号传导因营养过剩而受损，这改变了FXR的激活能力。
