Fatostatin inhibits SREBP2-mediated cholesterol uptake via LDLR against selective estrogen receptor α modulator-induced hepatic lipid accumulation. (25th September 2022)

• Record Type: Journal Article
• Authors: Li, Miao; Lu, Qian; Zhu, Yangping; Fan, Xue; Zhao, Wen; Zhang, Luyong; Jiang, Zhenzhou; Yu, Qinwei
• Is Part Of: Chemico-biological interactions. Volume 365(2022)
• Publication Date: 2022-09-25
• Subjects: Tamoxifen -- Fatty liver disease -- Fatostatin -- LDLR -- SREBP2; TMX Tamoxifen -- LDLR low density lipoprotein receptor -- SREBP2 sterol-regulatory element binding protein 2 -- Fato Fatostatin -- SERM selective estrogen receptor modulator -- TC total cholesterol -- TG triglyceride -- LDL-c low density lipoprotein cholesterol -- HDL-c high density lipoprotein cholesterol -- NEFA non-esterified fatty acid -- HMGCR Hydroxymethylglutaryl-CoA Reductase -- ER endoplasmic reticulum -- Scap SREBP cleavage-activating protein -- Insig1 insulin-induced gene 1 -- PCSK9 proprotein convertase subtilisin/kexin type 9 -- IDOL inducible degradation product of LDLR; Biochemistry -- Periodicals; Toxicological chemistry -- Periodicals; Biochemistry -- Periodicals; Biologie moléculaire -- Périodiques; Biochimie -- Périodiques; Toxicologie biochimique -- Périodiques; 572
• DOI: 10.1016/j.cbi.2022.110091
• Languages: English
• ISSNs: 0009-2797

Abstract

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. Graphical abstract: Image 1 Highlights: Hepatic cholesterol content increase was the main reason for tamoxifen induced NAFLD. Tamoxifen upregulated the expression and activity of LDLR leading to cholesterol transport into hepatocytes. The upregulation of LDLR by tamoxifen is mediated by SREBP2. Fatostatin could attenuate tamoxifen-induced hepatic cholesterol accumulation.