Stayrook Keith R, Bramlett Kelli S, Savkur Rajesh S, Ficorilli James, Cook Todd, Christe Michael E, Michael Laura F, Burris Thomas P
Lilly Research Laboratories, Lilly Corporate Center, Indianapolis, Indiana 46285, USA.
Endocrinology. 2005 Mar;146(3):984-91. doi: 10.1210/en.2004-0965. Epub 2004 Nov 24.
The farnesoid X receptor (FXR; NR1H4) is a nuclear hormone receptor that functions as the bile acid receptor. In addition to the critical role FXR plays in bile acid metabolism and transport, it regulates a variety of genes important in lipoprotein metabolism. We demonstrate that FXR also plays a role in carbohydrate metabolism via regulation of phosphoenolpyruvate carboxykinase (PEPCK) gene expression. Treatment of either H4IIE or MH1C1 rat hepatoma cell lines as well as primary rat or human hepatocytes with FXR agonists led to stimulation of PEPCK mRNA expression to levels comparable to those obtained with glucocorticoid receptor agonists. We examined the physiological significance of FXR agonist-induced enhancement of PEPCK expression in primary rat hepatocytes. In addition to inducing PEPCK expression in primary hepatocytes, FXR agonists stimulated glucose output to levels comparable to those observed with a glucocorticoid receptor agonist. Consistent with these observations, treatment of C57BL6 mice with GW4064 significantly increased hepatic PEPCK expression. Activation of FXR initiated a cascade involving induction of peroxisome proliferator-activated receptor alpha and TRB3 expression that is consistent with stimulation of PEPCK gene expression via interference with a pathway that may involve Akt-dependent phosphorylation of Forkhead/winged helix transcription factor (FOXO1). The FXR-peroxisome proliferator-activated receptor alpha-TRB3 pathway was conserved in rat hepatoma cell lines, mice, as well as primary human hepatocytes. Thus, in addition to its role in the regulation of lipid metabolism, FXR regulates carbohydrate metabolism.
法尼醇X受体（FXR；NR1H4）是一种核激素受体，作为胆汁酸受体发挥作用。除了在胆汁酸代谢和转运中发挥关键作用外，它还调节脂蛋白代谢中多种重要基因。我们证明FXR还通过调节磷酸烯醇式丙酮酸羧激酶（PEPCK）基因表达在碳水化合物代谢中发挥作用。用FXR激动剂处理H4IIE或MH1C1大鼠肝癌细胞系以及原代大鼠或人肝细胞，可使PEPCK mRNA表达水平升高，与用糖皮质激素受体激动剂处理后的水平相当。我们研究了FXR激动剂诱导原代大鼠肝细胞中PEPCK表达增强的生理意义。除了在原代肝细胞中诱导PEPCK表达外，FXR激动剂还能刺激葡萄糖输出，使其水平与用糖皮质激素受体激动剂处理后观察到的水平相当。与这些观察结果一致，用GW4064处理C57BL6小鼠可显著增加肝脏PEPCK表达。FXR的激活引发了一系列反应，包括过氧化物酶体增殖物激活受体α和TRB3表达的诱导，这与通过干扰可能涉及Akt依赖的叉头/翼状螺旋转录因子（FOXO1）磷酸化的途径刺激PEPCK基因表达一致。FXR-过氧化物酶体增殖物激活受体α-TRB3途径在大鼠肝癌细胞系、小鼠以及原代人肝细胞中是保守的。因此，除了在脂质代谢调节中的作用外，FXR还调节碳水化合物代谢。
