College of Pharmacy, Sookmyung Women's University, Seoul 04310, Republic of Korea.
Drug Information Research Institute, Sookmyung Women's University, Seoul 04310, Republic of Korea.
Cells. 2023 May 1;12(9):1292. doi: 10.3390/cells12091292.
Non-alcoholic fatty liver disease (NAFLD) refers to a range of conditions in which excess lipids accumulate in the liver, possibly leading to serious hepatic manifestations such as steatohepatitis, fibrosis/cirrhosis and cancer. Despite its increasing prevalence and significant impact on liver disease-associated mortality worldwide, no medication has been approved for the treatment of NAFLD yet. Liver X receptors α/β (LXRα and LXRβ) are lipid-activated nuclear receptors that serve as master regulators of lipid homeostasis and play pivotal roles in controlling various metabolic processes, including lipid metabolism, inflammation and immune response. Of note, NAFLD progression is characterized by increased accumulation of triglycerides and cholesterol, hepatic de novo lipogenesis, mitochondrial dysfunction and augmented inflammation, all of which are highly attributed to dysregulated LXR signaling. Thus, targeting LXRs may provide promising strategies for the treatment of NAFLD. However, emerging evidence has revealed that modulating the activity of LXRs has various metabolic consequences, as the main functions of LXRs can distinctively vary in a cell type-dependent manner. Therefore, understanding how LXRs in the liver integrate various signaling pathways and regulate metabolic homeostasis from a cellular perspective using recent advances in research may provide new insights into therapeutic strategies for NAFLD and associated metabolic diseases.
非酒精性脂肪性肝病（NAFLD）是指一系列肝脏内脂质蓄积过多的病症，可能导致严重的肝脏表现，如脂肪性肝炎、纤维化/肝硬化和肝癌。尽管其在全球范围内的患病率不断增加，并对与肝病相关的死亡率有重大影响，但目前尚无药物被批准用于治疗 NAFLD。肝 X 受体 α/β（LXRα 和 LXRβ）是脂激活的核受体，作为脂质稳态的主要调节剂，在控制包括脂质代谢、炎症和免疫反应在内的各种代谢过程中发挥关键作用。值得注意的是，NAFLD 的进展特征是甘油三酯和胆固醇的积累增加、肝脏从头合成脂质、线粒体功能障碍和炎症加剧，所有这些都高度归因于 LXR 信号的失调。因此，针对 LXR 可能为治疗 NAFLD 提供有前景的策略。然而，新出现的证据表明，调节 LXR 的活性具有各种代谢后果，因为 LXR 的主要功能在细胞类型依赖性方面明显不同。因此，从细胞角度理解肝脏中的 LXR 如何整合各种信号通路并调节代谢稳态，利用研究中的最新进展，可能为 NAFLD 和相关代谢性疾病的治疗策略提供新的见解。
