NRF2/HO-1 axis regulates fructose-induced lipid accumulation in hepatocytes

Abstract

ObjectiveNuclear factor erythroid 2-related factor 2 (NRF2), a key transcription factor involved in redox homeostasis, plays a critical role in preventing lipid peroxidation against various hepatic disorders, including metabolic dysfunction-associated fatty liver disease (MAFLD). Growing body of evidence suggests that excessive fructose consumption contributes to hepatic lipid accumulation.MethodsLipid accumulation in hepatocytes was induced by fructose treatment, while small interfering RNA (siRNA) transfection was used to suppress sterol regulatory element-binding protein-1c (SREBP-1c) expression. The size and the number of lipid droplets (LDs), as well as nuclear translocation of NRF2, were evaluated using microscopic analysis. Protein and mRNA expression levels were assessed by western blotting and qRT-PCR, respectively. Oxidative stress was analyzed using flow cytometry.ResultsFructose administration significantly increased LD accumulation and oxidative stress, accompanied by NRF2 activation and SREBP-1c expression. Silencing of SREBP-1c in fructose-treated hepatocytes markedly reduced LD accumulation and attenuated activation of the NRF2 signaling pathway. In contrast, inhibition of heme oxygenase-1 (HO-1) partially reversed these effects.ConclusionThe NRF2/HO-1 axis is involved in cellular adaptive response to fructose-induced oxidative stress and excessive LD accumulation.Significance statementElucidating the involvement of the NRF2/HO-1 axis between fructose metabolism and LD accumulation may provide valuable insights for the development of therapeutic strategies targeting fatty liver disorders.