Amelioration of Hepatic Steatosis by the Androgen Receptor Inhibitor EPI-001 in Mice and Human Hepatic Cells Is Associated with the Inhibition of CYP2E1

Int J Mol Sci. 2022 Dec 16;23(24):16063. doi: 10.3390/ijms232416063.

Abstract

Nonalcoholic fatty liver disease (NAFLD) is recognized as a metabolic disease characterized by hepatic steatosis. Despite the growing burden of NAFLD, approved pharmacological treatment is lacking. As an inhibitor of androgen receptor (AR), EPI-001 is being explored for the treatment of prostate cancer. This study aimed to investigate the potential of EPI-001 for treating NAFLD in free fatty acids (FFAs)-induced human hepatic cells and high-fat-high-sugar (HFHS)-feeding mice. Our results showed that EPI-001 reduced lipid accumulation in hepatic cells and ameliorated hepatic steatosis in mouse livers. Further exploration suggested that the effect of EPI-001 was associated with CYP2E1-mediated reduction of reactive oxygen species (ROS). This provides encouraging evidence for further studies on EPI-001 therapy for NAFLD.

Keywords: CYP2E1; EPI-001; NAFLD; hepatic steatosis.

MeSH terms

  • Animals
  • Cytochrome P-450 CYP2E1 / metabolism
  • Diet, High-Fat / adverse effects
  • Hepatocytes / metabolism
  • Humans
  • Lipid Metabolism
  • Liver / metabolism
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Non-alcoholic Fatty Liver Disease* / drug therapy
  • Non-alcoholic Fatty Liver Disease* / metabolism
  • Receptors, Androgen / metabolism

Substances

  • Cytochrome P-450 CYP2E1
  • EPI 001
  • Receptors, Androgen