Tamoxifen induced hepatic steatosis in high-fat feeding rats through SIRT1-Foxo1 suppression and LXR-SREBP1c activation

Miao Li; Yu Cai; Xi Chen; Luyong Zhang; Zhenzhou Jiang; Qinwei Yu

doi:10.1093/toxres/tfac043

Tamoxifen induced hepatic steatosis in high-fat feeding rats through SIRT1-Foxo1 suppression and LXR-SREBP1c activation

Toxicol Res (Camb). 2022 Jul 22;11(4):673-682. doi: 10.1093/toxres/tfac043. eCollection 2022 Aug.

Authors

Miao Li¹, Yu Cai¹, Xi Chen¹, Luyong Zhang^{1

2}, Zhenzhou Jiang^{1

3

4}, Qinwei Yu¹

Affiliations

¹ New Drug Screening Center, Jiangsu Center for Pharmacodynamics Research and Evaluation, China Pharmaceutical University, Nanjing 210009, China.
² Center for Drug Research and Development, Guangdong Pharmaceutical University, Guangzhou 510006, China.
³ Key Laboratory of Drug Quality Control and Pharmacovigilance, Ministry of Education, China Pharmaceutical University, Nanjing 210009 China.
⁴ Jiangsu Key Laboratory of Druggability of Biopharmaceuticals, China Pharmaceutical University, Nanjing 210009 China.

Abstract

Background: Clinically, long-term use of tamoxifen (TAM) would lead to fatty liver disease in breast cancer patients, especially obese women. However, the exact mechanism of TAM-induced hepatic steatosis is still unclear. Meanwhile, there is no drug to prevent and treat it.

Aims and methods: In view of silent information regulator 1 (SIRT1) playing a key role in hepatic lipid metabolism regulation, this study was conducted to investigate whether SIRT1 is a potential therapeutic target for TAM-induced hepatic steatosis. In this study, obese female Wistar rats fed with high-fat diet (HFD) for 15 weeks were given TAM (4, 8 mg/kg, intragastric) for 14 days. In vitro, human hepatocarcinoma cell line HepG2 was used to establish a high-fat model with 50 μM oleic acid and TAM (10 μM) was treated simultaneously for 72 h.

Results: The results showed that TAM was more likely to upregulate the expression of lipid synthetase that caused the increase of lipid content in HepG2 cells and rat liver. The expression of SIRT1 was downregulated both in vitro and in vivo. SIRT1 agonist SRT1720 (15 mg/kg, 30 mg/kg, i.p.) could resist TAM-induced hepatic lipid synthetase overexpression to relieve TAM-induced hepatic steatosis. Meanwhile, the upregulation of p-forkhead box O1 and LXRα induced by TAM was reversed by SRT1720.

Conclusions: These results indicated that TAM-induced hepatic steatosis was based on SIRT1-p-FoxO/LXRα-sterol regulatory element binding protein 1c pathway under HFD condition. SIRT1 agonist might be a potential therapeutic drug to relieve this side effect.

Highlights: Tamoxifen increased lipid synthesis and regulated lipid transport in HFD rat liver.p-FoxO1/LXRα-SREBP1c signaling was upregulated through the inhibition of SIRT1 in tamoxifen-induced hepatic steatosis under HFD condition.SIRT1 agonist SRT1720 could relieve tamoxifen-induced hepatic steatosis.

Keywords: SIRT1; SREBP1c; hepatic steatosis; tamoxifen.