Although iron is required for essential biological processes, excess iron is detrimental due to oxidative damage induced by iron-mediated Fenton reactions, which promote tissue injury. Cellular iron uptake, transport and storage must therefore be tightly regulated. This task is accomplished mainly through hepcidin, the key iron-regulatory hormone. Hepcidin is synthesized primarily in hepatocytes as a circulatory antimicrobial peptide. It controls iron metabolism by inhibiting iron absorption from the duodenum and iron release from reticuloendothelial macrophages. Besides synthesizing hepcidin, the liver plays an important role in maintaining iron homeostasis by serving as the main storage organ for excess iron. Patients with liver diseases frequently display disturbances of iron metabolism but the underlying mechanisms are unclear. Due to obesity epidemic worldwide, the incidence of nonalcoholic fatty liver disease (NAFLD) is on the rise. This study therefore focuses on the regulation of hepcidin in NAFLD. NAFLD is the hepatic manifestation of metabolic syndrome, which is characterized by visceral adiposity, dyslipidemia and insulin resistance. Both the level and distribution of iron in the livers of NAFLD patients have been shown to correlate with disease severity. NAFLD patients have also been reported to display changes in hepcidin expression. The significance and relevance of these alterations regarding NAFLD pathogenesis are unclear. Although impaired fatty acid metabolism and lipid accumulation in the liver are major contributors to the pathogenesis of NAFLD, the role of lipids or lipid derivatives in hepcidin regulation have not been investigated. The studies presented in this dissertation identified new and unique mechanisms of hepcidin gene regulation by saturated fatty acids and the biologically active lipid derivative, ceramide in human hepatoma cells. The post-transcriptional regulation of hepcidin expression by palmitic acid was mediated through AU-rich element binding protein, Human Antigen R (HuR) and novel class of protein kinase C isoforms. Ceramide, on the other hand, induced hepcidin transcription via inflammatory JAK/STAT3 signaling. Furthermore, by using high fat-fed hepcidin knockout mice as an in vivo model, I have implicated a role for hepcidin in the regulation of hepatic lipid metabolism, and characterized these mice as a potential experimental model to study liver injury in NAFLD
