Chiang John Y L, Ferrell Jessica M
Department of Integrative Medical Sciences, Northeast Ohio Medical University, 4029 SR 44, P.O. Box 95, Rootstown, OH, 44272, United States.
Department of Integrative Medical Sciences, Northeast Ohio Medical University, 4029 SR 44, P.O. Box 95, Rootstown, OH, 44272, United States.
Mol Cell Endocrinol. 2022 May 15;548:111618. doi: 10.1016/j.mce.2022.111618. Epub 2022 Mar 11.
In 1995, the nuclear hormone orphan receptor farnesoid X receptor (FXR, NR1H4) was identified as a farnesol receptor expressed mainly in liver, kidney, and adrenal gland of rats. In 1999, bile acids were identified as endogenous FXR ligands. Subsequently, FXR target genes involved in the regulation of hepatic bile acid synthesis, secretion, and intestinal re-absorption were identified. FXR signaling was proposed as a mechanism of feedback regulation of the rate-limiting enzyme for bile acid synthesis, cholesterol 7⍺-hydroxylase (CYP7A1). The primary bile acids synthesized in the liver are transformed to secondary bile acids by the gut microbiota. The gut-to-liver axis plays a critical role in the regulation of bile acid synthesis, composition and circulating bile acid pool size, which in turn regulates glucose, lipid, and energy metabolism. Dysregulation of bile acid metabolism and FXR signaling in the gut-to-liver axis contributes to metabolic diseases including obesity, diabetes, and non-alcoholic fatty liver disease. This review will cover the discovery of FXR as a bile acid sensor in the regulation of bile acid metabolism and as a metabolic regulator of lipid, glucose, and energy homeostasis. It will also provide an update of FXR functions in the gut-to-liver axis and the drug therapies targeting bile acids and FXR for the treatment of liver metabolic diseases.
1995年，核激素孤儿受体法尼醇X受体（FXR，NR1H4）被鉴定为一种主要在大鼠肝脏、肾脏和肾上腺中表达的法尼醇受体。1999年，胆汁酸被鉴定为内源性FXR配体。随后，鉴定出了参与肝脏胆汁酸合成、分泌和肠道重吸收调节的FXR靶基因。FXR信号传导被认为是胆汁酸合成限速酶胆固醇7α-羟化酶（CYP7A1）反馈调节的一种机制。肝脏中合成的初级胆汁酸被肠道微生物群转化为次级胆汁酸。肠-肝轴在胆汁酸合成、组成和循环胆汁酸池大小的调节中起关键作用，进而调节葡萄糖、脂质和能量代谢。肠-肝轴中胆汁酸代谢和FXR信号传导的失调会导致包括肥胖、糖尿病和非酒精性脂肪性肝病在内的代谢性疾病。本综述将涵盖FXR作为胆汁酸代谢调节中的胆汁酸传感器以及脂质、葡萄糖和能量稳态代谢调节剂的发现。它还将提供FXR在肠-肝轴中的功能以及针对胆汁酸和FXR治疗肝脏代谢疾病的药物疗法的最新进展。
