Wang H, Chen J, Hollister K, Sowers L C, Forman B M
Gonda Research Center, Beckman Research Institute, Department of Molecular Medicine, City of Hope National Medical Center, Duarte, California 91010, USA.
Mol Cell. 1999 May;3(5):543-53. doi: 10.1016/s1097-2765(00)80348-2.
The major metabolic pathway for elimination of cholesterol is via conversion to bile acids. In addition to this metabolic function, bile acids also act as signaling molecules that negatively regulate their own biosynthesis. However, the precise nature of this signaling pathway has been elusive. We have isolated an endogenous biliary component (chenodeoxycholic acid) that selectively activates the orphan nuclear receptor, FXR. Structure-activity analysis defined a subset of related bile acid ligands that activate FXR and promote coactivator recruitment. Finally, we show that ligand-occupied FXR inhibits transactivation from the oxysterol receptor LXR alpha, a positive regulator of cholesterol degradation. We suggest that FXR (BAR) is the endogenous bile acid sensor and thus an important regulator of cholesterol homeostasis.
胆固醇消除的主要代谢途径是转化为胆汁酸。除了这种代谢功能外，胆汁酸还作为信号分子对自身的生物合成起负调节作用。然而，这条信号通路的确切性质一直难以捉摸。我们分离出了一种内源性胆汁成分（鹅去氧胆酸），它能选择性激活孤儿核受体FXR。结构活性分析确定了一组相关胆汁酸配体，它们可激活FXR并促进共激活因子的募集。最后，我们发现配体结合的FXR可抑制氧甾醇受体LXRα的反式激活，LXRα是胆固醇降解的正调节因子。我们认为FXR（BAR）是内源性胆汁酸传感器，因此是胆固醇稳态的重要调节因子。
