Fuchs Claudia D, Traussnigg Stefan A, Trauner Michael
Hans Popper Laboratory of Molecular Hepatology, Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Vienna, Austria.
Semin Liver Dis. 2016 Feb;36(1):69-86. doi: 10.1055/s-0036-1571296. Epub 2016 Feb 12.
Nuclear receptors (NRs) are ligand-activated transcriptional regulators of several key metabolic processes including hepatic lipid and glucose metabolism, bile acid homeostasis, and energy expenditure as well as inflammation, fibrosis, and cellular proliferation in the liver. Dysregulation of these processes contributes to the pathogenesis and progression of nonalcoholic fatty liver disease (NAFLD). This places NRs at the forefront of novel therapeutic approaches for NAFLD. Some NRs are already pharmacologically targeted in metabolic disorders such as hyperlipidemia (peroxisomal proliferator-activated receptor α [PPARα], fibrates) and diabetes (PPARγ, glitazones) with potential applications for NAFLD. Other NRs with potential therapeutic implications are the vitamin D receptor (VDR) and xenobiotic sensors such as constitutive androstane receptor (CAR) and pregnane X receptor (PXR). Further new perspectives include combined ligands for NR isoforms such as PPARα/δ ligands. Other novel key players represent the nuclear bile acid receptor farnesoid X receptor (FXR; targeted by synthetic FXR ligands such as obeticholic acid) and RAR-related orphan receptor gamma two (RORγt). In this review the authors provide an overview of the preclinical and clinical evidence of current and future treatment strategies targeting NRs in metabolism, inflammation, and fibrogenesis of NAFLD.
核受体（NRs）是几种关键代谢过程的配体激活转录调节因子，这些过程包括肝脏脂质和葡萄糖代谢、胆汁酸稳态、能量消耗以及肝脏中的炎症、纤维化和细胞增殖。这些过程的失调会导致非酒精性脂肪性肝病（NAFLD）的发病机制和进展。这使得核受体成为NAFLD新型治疗方法的前沿靶点。一些核受体已经在高脂血症（过氧化物酶体增殖物激活受体α[PPARα]，贝特类药物）和糖尿病（PPARγ，噻唑烷二酮类药物）等代谢紊乱中作为药物靶点，对NAFLD可能具有潜在应用价值。其他具有潜在治疗意义的核受体是维生素D受体（VDR）和外源性物质传感器，如组成型雄甾烷受体（CAR）和孕烷X受体（PXR）。进一步的新观点包括针对NR亚型的联合配体，如PPARα/δ配体。其他新的关键参与者包括核胆汁酸受体法尼醇X受体（FXR；被合成FXR配体如奥贝胆酸靶向）和视黄酸相关孤儿受体γt（RORγt）。在这篇综述中，作者概述了目前和未来针对NAFLD代谢、炎症和纤维化中核受体的治疗策略的临床前和临床证据。
