Overexpression of Hepcidin Alleviates Steatohepatitis and Fibrosis in a Diet-induced Nonalcoholic Steatohepatitis

Background and Aims:Iron overload can contribute to the progression of nonalcoholic fatty liver disease(NAFLD)to nonalcoholic steatohepatitis(NASH).Hepcidin(Hamp),which is primarily synthesized in hepatocytes,is a key reg-ulator of iron metabolism.However,the role of Hamp in NASH remains unclear.Therefore,we aimed to elucidate the role of Hamp in the pathophysiology of NASH.Methods:Male mice were fed a choline-deficient L-amino acid-defined(CDAA)diet for 16 weeks to establish the mouse NASH model.A choline-supplemented amino acid-defined(CSAA)diet was used as the control diet.Recombinant adeno-asso-ciated virus genome 2 serotype 8 vector expressing Hamp(rAAV2/8-Hamp)or its negative control(rAAV2/8-NC)was administered intravenously at week 8 of either the CDAA or CSAA diet.Results:rAAV2/8-Hamp treatment markedly decreased liver weight and improved hepatic steatosis in the CDAA-fed mice,accompanied by changes in lipogenesis-related genes and adiponectin expression.Compared with the control group,rAAV2/8-Hamp therapy attenuated liver damage,with mice exhibiting reduced histological NAFLD inflammation and fibrosis,as well as lower levels of liver enzymes.Moreover,α-smooth muscle actin-positive acti-vated hepatic stellate cells(HSCs)and CD68-postive mac-rophages increased in number in the CDAA-fed mice,which was reversed by rAAV2/8-Hamp treatment.Consistent with the in vivo findings,overexpression of Hamp increased adi-ponectin expression in hepatocytes and Hamp treatment inhibited HSC activation.Conclusions:Overexpression of Hamp using rAAV2/8-Hamp robustly attenuated liver stea-tohepatitis,inflammation,and fibrosis in an animal model of NASH,suggesting a potential therapeutic role for Hamp.