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

Lena Seidemann,Daniel Seehofer,Anne Krüger,Georg Damm,Victoria Kegel-Hübner

doi:10.3390/molecules26041156

Abstract

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 PPARα 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. PPARα protein expression was induced in steatotic PHHs, accompanied by an increase in CPT1L and ACSL1 mRNA. Genistein treatment increased PPARα protein expression only in control PHHs, while CPTL1 and ACSL1 were unchanged and PPARα 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 PPARα were abolished by high hepatic lipid levels.

Highlights

Nonalcoholic fatty liver disease (NAFLD) is the most common cause of chronic liver disease worldwide, with a global prevalence of approximately 25% [1,2]. It is considered the hepatic manifestation of metabolic syndrome and comprises a wide spectrum of liver impairments, starting with hepatic steatosis, which can progress to more severe liver damage, e.g., steatohepatitis (NASH), fibrosis and cirrhosis [3]
Our results show that our in vitro steatosis model was characterized by high lipid accumulation accompanied by mild lipotoxic effects and a lipid-related shift in signaling towards lipid metabolism
Drugs currently used in NAFLD management only treat individual etiological factors that contribute to its onset and progression [24]

Summary

Introduction

Nonalcoholic fatty liver disease (NAFLD) is the most common cause of chronic liver disease worldwide, with a global prevalence of approximately 25% [1,2]. It is considered the hepatic manifestation of metabolic syndrome and comprises a wide spectrum of liver impairments, starting with hepatic steatosis, which can progress to more severe liver damage, e.g., steatohepatitis (NASH), fibrosis and cirrhosis [3]. The first stage of NAFLD, is marked by intracellular accumulation of triglycerides due to increased uptake of free fatty acids (FFAs), augmented de novo lipogenesis and impaired fatty acid β-oxidation [7,8,9]. The underlying molecular mechanisms are not fully understood but are currently being extensively studied, with the goal of a possible drug target to enable pharmacological NAFLD treatment [10]

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