New Drug Screening Center, Jiangsu Center for Pharmacodynamics Research and Evaluation, China Pharmaceutical University, Nanjing, 210009, China.
New Drug Screening Center, Jiangsu Center for Pharmacodynamics Research and Evaluation, China Pharmaceutical University, Nanjing, 210009, China; Center for Drug Research and Development, Guangdong Pharmaceutical University, Guangzhou, 510006, China.
Chem Biol Interact. 2022 Sep 25;365:110091. doi: 10.1016/j.cbi.2022.110091. Epub 2022 Aug 6.
Estrogen receptor α (ERα) plays a key role in the adaptive response of liver metabolism to energy demands, especially in controlling lipid metabolism. Tamoxifen (TMX), a main drug for the treatment of ER-positive breast cancer in clinical, is a selective ER modulator (SERM). However, accordingly, the long-term use of TMX would lead to nonalcoholic fatty liver (NAFLD) in clinical, which had no definite treatment up to now. Fatostatin (Fato), an inhibitor of sterol-regulatory element binding protein 2 (SREBP2), was reported as a synergistic inhibitor of ER-positive breast cancer with TMX, but the hepatic lipid regulation of this combination is still unknown. Herein, we aimed to explore the effect and mechanism of Fato against TMX-induced NAFLD. The results identified that hepatic cholesterol content increase was the main reason for TMX-induced NAFLD. It was caused by the upregulation of circulating cholesterol uptake mediated by low density lipoprotein receptor (LDLR) in liver, which resulted from the activation of SREBP2. Meanwhile, Fato could inhibit activation of SREBP2-LDLR pathway, alleviating TMX-induced hepatic cholesterol accumulation. In summary, these results provided a new insight into the mechanism of TMX-induced NAFLD. Moreover, it supported the combination of Fato and TMX for the treatment of ER-positive breast cancer to reduce the adverse effect of TMX in clinical.
雌激素受体 α（ERα）在肝脏代谢对能量需求的适应性反应中起着关键作用，尤其是在控制脂代谢方面。他莫昔芬（TMX）是临床治疗雌激素受体阳性乳腺癌的主要药物，是一种选择性雌激素受体调节剂（SERM）。然而，相应地，TMX 的长期使用会导致临床中的非酒精性脂肪性肝病（NAFLD），目前尚无明确的治疗方法。Fatostatin（Fato）是固醇调节元件结合蛋白 2（SREBP2）的抑制剂，被报道为与 TMX 协同抑制雌激素受体阳性乳腺癌的药物，但这种联合用药对肝脏脂质的调节作用尚不清楚。在此，我们旨在探讨 Fato 对 TMX 诱导的 NAFLD 的作用及其机制。结果表明，肝胆固醇含量增加是 TMX 诱导 NAFLD 的主要原因。这是由于肝脏中低密度脂蛋白受体（LDLR）介导的循环胆固醇摄取增加所致，而 LDLR 的增加是由于 SREBP2 的激活。同时，Fato 可以抑制 SREBP2-LDLR 通路的激活，从而减轻 TMX 诱导的肝胆固醇蓄积。总之，这些结果为 TMX 诱导的 NAFLD 机制提供了新的见解。此外，它支持 Fato 和 TMX 的联合用于治疗雌激素受体阳性乳腺癌，以减少 TMX 在临床上的不良反应。
