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Regulation of bile acid homeostasis by the nuclear bile acid receptor FXR and fibroblast growth factor 15

机译:核胆汁酸受体FXR和成纤维细胞生长因子15调节胆汁酸性稳态

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The nuclear receptors comprise a superfamily of ligand-activated transcription factors that includes the steroid, thyroid hormone and retinoid receptors as well as receptors for xenobiotics, fatty acids and cholesterol metabolites3. The farnesoid X receptor (FXR) is a nuclear receptor that was named based on its weak, non-physiological activation by the terpenoid farnesol2. Subsequent studies showed that FXR is activated efficiently by physiological concentrations of the primary bile acids cholic acid and chenodeoxycholic acid3"5. FXR is highly expressed in the liver, intestine and kidney, where it coordinates bile acid homeostasis by binding to DNA response elements as a heterodimer with the retinoid X receptor (RXR). The physiological role of FXR as a bile acid receptor was confirmed in FXR-knockout (KO) mice: these animals exhibit dramatic changes in bile acid homeostasis, including a marked increase in bile acid synthesis, an expanded bile acid poof, and changes in the composition of their bile acids6' . They are also hypersensitive to the administration of exogenous cholic acid, which causes elevated serum and hepatic bile acid concentrations and severe liver damage7.
机译:核受体包含一个超家族的配体活化转录因子,包括类固醇,甲状腺激素和类视黄曲面受体以及异种液,脂肪酸和胆固醇代谢物3的受体。法呢X受体(FXR)是一种核受体,该核受体是根据Terpenoid法呢道2的弱,非生理活化命名的核受体。随后的研究表明,通过原发性胆汁酸胆酸和赤铁氧胆酸3“5的生理浓度有效地激活FXR。FXR在肝脏,肠和肾中高度表达,在其中通过与DNA响应元素结合时坐标偶联胆酸稳态异源二聚体与类视黄醇X受体(RXR)FXR作为生理作用胆汁酸受体在FXR敲除(KO)小鼠中证实:这些动物表现出胆汁酸内环境稳定,包括在胆汁酸合成的显着增加的剧烈变化,膨胀的胆汁酸POOF,以及它们的胆汁酸的组合物的变化。它们对外源胆酸的给药也过敏,这导致血清和肝胆汁酸浓度升高和严重肝脏损伤7。

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