Institute for Diabetes, Obesity, and Metabolism, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA; Division of Endocrinology, Diabetes, and Metabolism, Department of Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA.
Institute for Diabetes, Obesity, and Metabolism, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA; Division of Endocrinology, Diabetes, and Metabolism, Department of Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA; Department of Genetics, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA.
Mol Metab. 2021 Aug;50:101119. doi: 10.1016/j.molmet.2020.101119. Epub 2020 Nov 18.
As a result of a sedentary lifestyle and excess food consumption in modern society, non-alcoholic fatty liver disease (NAFLD) characterized by fat accumulation in the liver is becoming a major disease burden. Non-alcoholic steatohepatitis (NASH) is an advanced form of NAFLD characterized by inflammation and fibrosis that can lead to hepatocellular carcinoma and liver failure. Nuclear receptors (NRs) are a family of ligand-regulated transcription factors that closely control multiple aspects of metabolism. Their transcriptional activity is modulated by various ligands, including hormones and lipids. NRs serve as potential pharmacological targets for NAFLD/NASH and other metabolic diseases.
In this review, we provide a comprehensive overview of NRs that have been studied in the context of NAFLD/NASH with a focus on their transcriptional regulation, function in preclinical models, and studies of their clinical utility.
The transcriptional regulation of NRs is context-dependent. During the dynamic progression of NAFLD/NASH, NRs play diverse roles in multiple organs and different cell types in the liver, which highlights the necessity of targeting NRs in a stage-specific and cell-type-specific manner to enhance the efficacy and safety of treatment methods.
由于现代社会生活方式久坐不动和食物摄入过量，以肝脏脂肪堆积为特征的非酒精性脂肪性肝病（NAFLD）正成为主要疾病负担。非酒精性脂肪性肝炎（NASH）是一种进展性 NAFLD 形式，其特征为炎症和纤维化，可导致肝细胞癌和肝功能衰竭。核受体（NRs）是一类配体调控的转录因子家族，它们密切控制着代谢的多个方面。它们的转录活性受到各种配体的调节，包括激素和脂质。NRs 是治疗 NAFLD/NASH 和其他代谢性疾病的潜在药物靶点。
在这篇综述中，我们全面概述了在 NAFLD/NASH 背景下研究的 NRs，重点介绍了它们的转录调控、在临床前模型中的功能以及对其临床应用的研究。
NRs 的转录调控是上下文相关的。在 NAFLD/NASH 的动态进展过程中，NRs 在肝脏的多个器官和不同细胞类型中发挥着不同的作用，这突出了以阶段特异性和细胞类型特异性方式靶向 NRs 以提高治疗方法的疗效和安全性的必要性。
