核受体在非酒精性脂肪肝中的研究进展

Progress of nuclear receptor in nonalcoholic fatty liver disease

核受体(NRs)是葡萄糖代谢,胆汁酸代谢,能量消耗以及肝炎、肝纤维化和肝细胞增殖等主要代谢过程的配体激活转录调节因子。这些过程的失调促进非酒精性脂肪性肝病(NAFLD)的发病和发展。这使NRs处于研究NAFLD的新颖治疗方法的前沿。某些NRs药物已经可以针对性的治疗代谢障碍,如氧化物酶体增殖物激活受体α(PPARα)激动剂贝特类药物治疗高脂血症以及氧化物酶体增殖物激活受体γ(PPARγ)激动剂格列酮类药物治疗糖尿病,并且这些药物潜在应用于NAFLD。其他具有潜在治疗作用的NRs有维生素D受体(VDR)和外源性传感器,如组成型雄烷受体(CAR)和孕烷X受体(PXR)。之后又发现NRs亚型的组合配体,如PPARα/δ配体。其他新颖的关键因子有核胆汁酸受体、法尼醇X受体(FXR,其目的是合成FXR配体,如奥贝胆酸)和RAR相关孤儿素受体γ2(RORγt)。本综述概述了NRs对NAFLD的代谢、炎症和纤维化的治疗策略。

Nuclear receptors （NRs） are ligand activated transcription factor that regulates several main metabolic processes, including the liver lipid, glucose metabolism, bile acid metabolism, energy consumption, hepatitis, liver fibrosis, and hepatocyte proliferation. The maladjustment of these processes contributes to the onset and development of nonalcoholic fatty liver disease （NAFLD）. Therefore NRs become the forefront of the novel treatment of NAFLD. Some NRs are already pharmacologically targeted in metabolic disorders such as hyperlipidemia （peroxisomal proliferatoractivated receptor a [PPARa], fibrates）, and diabetes （PPARγ,glitazones） with potential applications for NAFLD. Other NRs with potential therapeutic implications include vitamin D receptor （VDR） and xenobiotic sensors such as constitutive androstane receptor （CAR） and pregnane X receptor （PXR）. New perspectives include combined ligands for NR isoforms such as PPARα/δ ligands. Other novel key players cover the nuclear bile acid receptor farnesoid X receptor （FXR） and RAR-related orphan receptor γ2 （PPARγ）. This review summarizes the treatment strategies of NRs for metabolism, inflammation, and fibrogenesis of NAFLD.