非酒精性脂肪肝（NAFLD）和慢性乙型肝炎是全球两大主要肝病。目前，合并NAFLD的乙肝患者，除控制体重改善糖脂代谢外，仍以抗病毒药物治疗为主，但NAFLD状态下抗乙肝药物药效变化的机制研究尚不明确。恩替卡韦（ETV）是最主要抗乙肝药物，体内以离子形式存在，依赖转运体进入肝细胞发挥药效。我们的前期研究结果提示肝脏有机阴离子转运体（OAT）2和平衡性核苷转运体（ENT）1在肝细胞摄取ETV中发挥主要作用，且NAFLD模型小鼠肝脏mOat2、mEnt1表达下调。本项目将在此基础上，从细胞和整体动物水平证实NAFLD对ETV药效的影响，多角度阐明转运体介导的ETV肝摄取机制，通过研究NAFLD对肝OAT2、ENT1表达的调控进而改变ETV肝组织分布及药代动力学，探究NAFLD影响ETV药效的机制。本研究为提高合并NAFLD慢性乙型肝炎患者的ETV药效提供理论依据与指导。

Non-alcoholic fatty liver disease (NAFLD) and chronic hepatitis B are the two major liver diseases in the world. In addition to weight management to improve glycolipid metabolism, antiviral therapy is still predominated in patients with hepatitis B complicated by NAFLD. However, the mechanism by which NAFLD affects the efficacy of antivirals against hepatitis B virus (HBV) remains unclear. Entecavir (ETV) is a first-line antiviral drug against HBV, which is positively charged at physiological conditions and relies on the transporter into hepatocytes. Our previous studies indicated that organic anion transporter (OAT) 2 and equilibrative nucleotide transporter (ENT) 1 play a major role in the uptake of ETV by hepatocytes, whereas the expression of mOat2 and mEnt1 in the liver of mouse NAFLD model was repressed. Based on these results, we will demonstrate the effect of NAFLD on the efficacy of ETV both in vitro and in vivo, and elucidate the mechanism of hepatic uptake of ETV mediated by transporter. The aim of this project is to explore the mechanism of decreased efficacy of ETV in NAFLD by clarifying the expression changes of hepatic OAT2 and ENT1 that further affect the ETV distribution in liver. The information obtained in this study may provide a basis for the use of ETV in patients with hepatitis B complicated by NAFLD.