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  3. Tamoxifen upregulates the peroxisomal β-oxidation enzyme Enoyl CoA hydratase and 3-hydroxyacyl CoA hydratase ameliorating hepatic lipid accumulation in mice

Tamoxifen upregulates the peroxisomal β-oxidation enzyme Enoyl CoA hydratase and 3-hydroxyacyl CoA hydratase ameliorating hepatic lipid accumulation in mice

  • Int J Biochem Cell Biol. 2024 May 9:172:106585. doi: 10.1016/j.biocel.2024.106585.
Ziling Zhang 1,  Qinqin Yang 2,  Ming Jin 3,  Jie Wang 4,  Yuanyuan Chai 5,  Luyong Zhang 6,  Zhenzhou Jiang 7,  Qinwei Yu 8
Affiliations

Affiliations

  • 1 New Drug Screening and Pharmacodynamics Evaluation Center, Jiangsu Center for Pharmacodynamics Research and Evaluation, State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 210009, China. Electronic address: 15961640897@163.com.
  • 2 New Drug Screening and Pharmacodynamics Evaluation Center, Jiangsu Center for Pharmacodynamics Research and Evaluation, State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 210009, China. Electronic address: 3222071653@stu.cpu.edu.cn.
  • 3 New Drug Screening and Pharmacodynamics Evaluation Center, Jiangsu Center for Pharmacodynamics Research and Evaluation, State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 210009, China. Electronic address: jm2281433772@163.com.
  • 4 New Drug Screening and Pharmacodynamics Evaluation Center, Jiangsu Center for Pharmacodynamics Research and Evaluation, State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 210009, China. Electronic address: limyoona9097@163.com.
  • 5 New Drug Screening and Pharmacodynamics Evaluation Center, Jiangsu Center for Pharmacodynamics Research and Evaluation, State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 210009, China. Electronic address: cyy_pharm@163.com.
  • 6 New Drug Screening and Pharmacodynamics Evaluation Center, Jiangsu Center for Pharmacodynamics Research and Evaluation, State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 210009, China; Center for Drug Research and Development, Guangdong Pharmaceutical University, Guangzhou 510006, China; Key Laboratory of Drug Quality Control and Pharmacovigilance, Ministry of Education, China Pharmaceutical University, Nanjing 210009, China. Electronic address: lyzhang@cpu.edu.cn.
  • 7 New Drug Screening and Pharmacodynamics Evaluation Center, Jiangsu Center for Pharmacodynamics Research and Evaluation, State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 210009, China; Key Laboratory of Drug Quality Control and Pharmacovigilance, Ministry of Education, China Pharmaceutical University, Nanjing 210009, China. Electronic address: beaglejiang@cpu.edu.cn.
  • 8 New Drug Screening and Pharmacodynamics Evaluation Center, Jiangsu Center for Pharmacodynamics Research and Evaluation, State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 210009, China. Electronic address: yuqinwei7213@cpu.edu.cn.
PMID: 38734232 DOI: 10.1016/j.biocel.2024.106585
Abstract

Tamoxifen is an Estrogen receptor Modulator that has been reported to alleviate hepatic lipid accumulation in mice, but the mechanism is still unclear. Peroxisome fatty acid β-oxidation is the main metabolic pathway for the overload of long-chain fatty acids. As long-chain fatty acids are a cause of hepatic lipid accumulation, the activation of peroxisome fatty acid β-oxidation might be a novel therapeutic strategy for metabolic associated fatty liver disease. In this study, we investigated the mechanism of tamoxifen against hepatic lipid accumulation based on the activation of peroxisome fatty acid β-oxidation. Tamoxifen reduced liver long-chain fatty acids and relieved hepatic lipid accumulation in high fat diet mice without sex difference. In vitro, tamoxifen protected primary hepatocytes against palmitic acid-induced lipotoxicity. Mechanistically, the RNA-sequence of hepatocytes isolated from the liver revealed that peroxisome fatty acid β-oxidation was activated by tamoxifen. Protein and mRNA expression of enoyl CoA hydratase and 3-hydroxyacyl CoA hydratase were significantly increased in vivo and in vitro. Small interfering RNA enoyl CoA hydratase and 3-hydroxyacyl CoA hydratase in primary hepatocytes abolished the therapeutic effects of tamoxifen in lipid accumulation. In conclusion, our results indicated that tamoxifen could relieve hepatic lipid accumulation in high fat diet mice based on the activation of enoyl CoA hydratase and 3-hydroxyacyl CoA hydratase-mediated peroxisome fatty acids β-oxidation.

Keywords

Enoyl CoA hydratase and 3-hydroxyacyl CoA hydratase; Long-chain fatty acids; Metabolic associated fatty liver disease; Peroxisome fatty acid β-oxidation; Tamoxifen.

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