Farnesoid X receptor is essential for normal glucose homeostasis
Farnesoid X receptor is essential for normal glucose homeostasis
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DOI：
10.1172/jci25604
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发表时间：
2006-04-01
影响因子：
15.9
通讯作者：
Moore, DD
中科院分区：
文献类型：
--
作者：
Ma, K;Saha, PK;Moore, DD
胆汁酸受体法尼醇X受体（FXR; NR 1H 4）是胆汁酸和脂质代谢的中心调节剂。我们在这里表明，FXR在葡萄糖稳态中起着关键的调节作用。FXR基因敲除小鼠出现严重脂肪肝和循环FFA升高，这与血清葡萄糖升高以及葡萄糖和胰岛素耐量受损相关。他们的胰岛素抵抗证实了高胰岛素正葡萄糖钳夹，这表明减弱抑制肝脏葡萄糖的生产胰岛素和减少外周葡萄糖处置。在FXR-/-骨骼肌和肝脏中，胰岛素信号传导途径的多个步骤明显减弱。在不表达FXR的骨骼肌中，甘油三酯和FFA水平增加，我们认为它们的抑制作用导致了该组织的胰岛素抵抗。与FXR-/-小鼠中的结果相反，WT小鼠中FXR的胆汁酸激活抑制了致炎基因的表达并降低了血清葡萄糖。在FXR-/-和小异源二聚体伴侣缺失（SHP-/-）小鼠中不存在这种抑制，表明先前描述的FXR-SHP核受体级联也靶向葡萄糖代谢。总之，我们的研究结果确定了FXR-SHP级联介导的脂质和葡萄糖代谢之间的联系。
The bile acid receptor farnesoid X receptor (FXR; NR1H4) is a central regulator of bile acid and lipid metabolism. We show here that FXR plays a key regulatory role in glucose homeostasis. FXR-null mice developed severe fatty liver and elevated circulating FFAs, which was associated with elevated serum glucose and impaired glucose and insulin tolerance. Their insulin resistance was confirmed by the hyperinsulinemic euglycemic clamp, which showed attenuated inhibition of hepatic glucose production by insulin and reduced peripheral glucose disposal. in FXR-/- skeletal muscle and liver, multiple steps in the insulin signaling pathway were markedly blunted. In skeletal muscle, which does not express FXR, triglyceride and FFA levels were increased, and we propose that their inhibitory effects account for insulin resistance in that tissue. In contrast to the results in FXR-/- mice, bile acid activation of FXR in WT mice repressed expression of gluconeogenic genes and decreased serum glucose. The absence of this repression in both FXR-/- and small heterodimer partner-null (SHP-/-) mice demonstrated that the previously described FXR-SHP nuclear receptor cascade also targets glucose metabolism. Taken together, our results identify a link between lipid and glucose metabolism mediated by the FXR-SHP cascade.