核受体FXR调控肝脏脂质代谢研究进展

Advances in the Regulation of Hepatic Lipid Metabolism by the Nuclear Receptor FXR

肝脂肪变性是肝脏摄取的游离脂肪酸(即脂肪酸摄取和脂质从头合成增加)超过其自身处置能力(即脂肪酸β氧化减少和脂质转运不足)的结果。因此,恢复肝脏脂质稳态是目前以脂肪变性为主要病理表现的肝脏疾病的主要治疗策略。法尼酯X受体(FXR)是配体激活的核受体超家族中的一个重要成员,众多研究表明其在调节胆汁酸稳态、糖类及脂质代谢、炎症、肠道菌群和肝脏再生等方面发挥重要作用。综述FXR及其翻译后修饰对肝脏脂质摄取、合成、氧化及转运等多种途径的调控作用,并概述以FXR为靶标的小分子配体药物的开发现状,以期为进一步阐明以肝脂肪变性为特点的肝脏疾病的分子机制提供参考。

Hepatic steatosis is a consequence of lipid acquisition(i.e.increased free fatty acid uptake and de novo lipogenesis)exceeding lipid disposal(i.e.decreased fatty acidβ-oxidation and relatively inadequate lipoprotein output).Restoration of hepatic lipid homeostasis,therefore,is currently the main therapeutic strategy for liver diseases in which steatosis is the main pathological manifestation.Farnesoid X receptor(FXR)is a major member of the ligand-activated nuclear receptor superfamily,and numerous studies have shown its important role in regulating bile acid homeostasis,glucose and lipid metabolism,inflammation,intestinal bacterial growth,and hepatic regeneration.This paper reviews the regulatory roles of FXR and its post-translational modifications on various pathways of hepatic lipid uptake,synthesis,oxidation and transport,and outlines the current status of development of small molecule ligand drugs targeting FXR,with the aim of providing insights to further elucidate the molecular mechanisms of liver diseases characterized by hepatic steatosis.