Lack of hepcidin expression attenuates steatosis and causes fibrosis in the liver

Sizhao Lu, Robert G. Bennett, Kusum K. Kharbanda, Duygu Dee Harrison-Findik

Research output: Contribution to journalArticlepeer-review

17 Scopus citations

Abstract

AIM: To investigate the role of key iron-regulatory protein, hepcidin in non-alcoholic fatty liver disease (NAFLD). METHODS: Hepcidin (Hamp1) knockout and floxed control mice were administered a high fat and high sucrose (HFS) or a regular control diet for 3 or 7 mo. Steatosis, triglycerides, fibrosis, protein and gene expression in mice livers were determined by histological and biochemical techniques, western blotting and real-time polymerase chain reaction. RESULTS: Knockout mice exhibited hepatic iron accumulation. Despite similar weight gains, HFS feeding induced hepatomegaly in floxed, but not knockout, mice. The livers of floxed mice exhibited higher levels of steatosis, triglycerides and c-Jun N-terminal kinase (JNK) phosphorylation than knockout mice. In contrast, a significant increase in fibrosis was observed in knockout mice livers within 3 mo of HFS administration. The hepatic gene expression levels of sterol regulatory element-binding protein-1c and fat-specific protein-27, but not peroxisome proliferator-activated receptor-alpha or microsomal triglyceride transfer protein, were attenuated in HFS-fed knockout mice. Knockout mice fed with regular diet displayed increased carnitine palmitoyltransferase-1a and phosphoenolpyruvate carboxykinase-1 but decreased glucose-6-phosphatase expression in the liver. In summary, attenuated steatosis correlated with decreased expression of lipogenic and lipid storage genes, and JNK phosphorylation. Deletion of Hamp1 alleles per se modulated hepatic expression of beta-oxidation and gluconeogenic genes. CONCLUSION: Lack of hepcidin expression inhibits hepatic lipid accumulation and induces early development of fibrosis following high fat intake. Hepcidin and iron may play a role in the regulation of metabolic pathways in the liver, which has implications for NAFLD pathogenesis.

Original languageEnglish (US)
Pages (from-to)211-225
Number of pages15
JournalWorld Journal of Hepatology
Volume8
Issue number4
DOIs
StatePublished - Feb 8 2016

Keywords

  • Hamp
  • Iron
  • Metabolic genes
  • Non-alcoholic fatty liver disease
  • Non-alcoholic steatohepatitis
  • Steatohepatitis
  • Steatosis

ASJC Scopus subject areas

  • Hepatology

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