2. Academic Validation
  3. Fatostatin inhibits SREBP2-mediated cholesterol uptake via LDLR against selective estrogen receptor α modulator-induced hepatic lipid accumulation

Fatostatin inhibits SREBP2-mediated cholesterol uptake via LDLR against selective estrogen receptor α modulator-induced hepatic lipid accumulation

  • Chem Biol Interact. 2022 Sep 25;365:110091. doi: 10.1016/j.cbi.2022.110091.
Miao Li 1,  Qian Lu 1,  Yangping Zhu 1,  Xue Fan 1,  Wen Zhao 1,  Luyong Zhang 2,  Zhenzhou Jiang 3,  Qinwei Yu 4
Affiliations

Affiliations

  • 1 New Drug Screening Center, Jiangsu Center for Pharmacodynamics Research and Evaluation, China Pharmaceutical University, Nanjing, 210009, China.
  • 2 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.
  • 3 New Drug Screening Center, Jiangsu Center for Pharmacodynamics Research and Evaluation, China Pharmaceutical University, Nanjing, 210009, China; Key Laboratory of Drug Quality Control and Pharmacovigilance, Ministry of Education, China Pharmaceutical University, Nanjing, 210009, China; Jiangsu Key Laboratory of Druggability of Biopharmaceuticals, Nanjing, 210009, China. Electronic address: beaglejiang@cpu.edu.cn.
  • 4 New Drug Screening Center, Jiangsu Center for Pharmacodynamics Research and Evaluation, China Pharmaceutical University, Nanjing, 210009, China. Electronic address: yuqinwei7213@cpu.edu.cn.
PMID: 35944649 DOI: 10.1016/j.cbi.2022.110091
Abstract

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.

Keywords

Fatostatin; Fatty liver disease; LDLR; SREBP2; Tamoxifen.

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