Influence of Genistein on Hepatic Lipid Metabolism in an In Vitro Model of Hepatic Steatosis

Nonalcoholic fatty liver disease (NAFLD) is among the leading causes of end-stage liver disease. The impaired hepatic lipid metabolism in NAFLD is exhibited by dysregulated PPAR alpha and SREBP-1c signaling pathways, which are central transcription factors associated with lipid degradation and de novo lipogenesis. Despite the growing prevalence of this disease, current pharmacological treatment options are unsatisfactory. Genistein, a soy isoflavone, has beneficial effects on lipid metabolism and may be a candidate for NAFLD treatment. In an in vitro model of hepatic steatosis, primary human hepatocytes (PHHs) were incubated with free fatty acids (FFAs) and different doses of genistein. Lipid accumulation and the cytotoxic effects of FFAs and genistein treatment were evaluated by colorimetric and enzymatic assays. Changes in lipid homeostasis were examined by RT-qPCR and Western blot analyses. PPAR alpha protein expression was induced in steatotic PHHs, accompanied by an increase in CPT1L and ACSL1 mRNA. Genistein treatment increased PPAR alpha protein expression only in control PHHs, while CPTL1 and ACSL1 were unchanged and PPAR alpha mRNA was reduced. In steatotic PHHs, genistein reversed the increase in activated SREBP-1c protein. The model realistically reflected the molecular changes in hepatic steatosis. Genistein suppressed the activation of SREBP-1c in steatotic hepatocytes, but the genistein-mediated effects on PPAR alpha were abolished by high hepatic lipid levels.

Automated summary

Nonalcoholic fatty liver disease (NAFLD) is a leading cause of end-stage liver disease, with unsatisfactory pharmacological treatment options available. Genistein, a soy isoflavone, shows beneficial effects on lipid metabolism and may be a candidate for NAFLD treatment. In an in vitro model, genistein treatment affects PPAR alpha and SREBP-1c signaling pathways, playing a significant role in hepatic lipid metabolism.