他莫昔芬（TAM）是治疗ERα阳性乳腺癌的一线药物，临床使用可致高发的非酒精性脂肪性肝病（NAFLD），可进展为脂肪性肝炎和肝硬化。研究表明TAM可促进脂肪酸合成和抑制脂肪酸β氧化，但是其上游的机制并不明确。前期工作表明TAM导致肝脏脂质蓄积与肝脏SIRT1的调控作用有关，SIRT1激动剂可减轻肝脂质蓄积。本研究在前期基础上，进一步考察TAM经SIRT1-ERα/AMPK信号通路诱发NAFLD的作用机制，阐明TAM通过调控CCAR1/DBC1，抑制ERα/LXRα，进而激活SREBP-1的机制；同时，探究TAM抑制SIRT1活性，及对AMPK/SREBP-1通路的作用，阐明糖脂代谢途径在脂质蓄积过程中的机制。研究结果有望阐明TAM可通过非经典雌激素效应途径致NAFLD的新机制，为TAM毒副反应的早期预警，临床安全用药，以及NAFLD治疗药物的研发提供理论依据。

Tamoxifen (TAM) is a first-line drug for the treatment of ERα-positive breast cancer, which can cause high incidence of nonalcoholic fatty liver disease (NAFLD) leading to severe hepatitis and cirrhosis. It has been shown that TAM could promote fatty acid synthesis and inhibit fatty acid β-oxidation. However, mechanism of its upstream pathway is not clear. In our previous study, the results showed that TAM-induced lipid accumulation is related to the regulation of SIRT1， which could be reduced by SIRT1 agonist. According to these findings, this study aims to further explore the mechanism of TAM-induced lipid accumulation via SIRT1-ERα/AMPK signaling pathways and to explain the mechanism that TAM inhibits ERα/LXR by regulating CCAR1/DBC1, which leads to SREBP-1 activation. Meanwhile, effect of TAM on AMPK/SREBP-1 pathway by SIRT1 inhibition is expected to explore, and the mechanism of glucolipid metabolism in the process of lipid accumulation would be explained. This study could provide a theoretical basis for the early warning of TAM side effects, clinical safety medication and the development of NAFLD therapeutic drugs.