Non alcoholic fatty liver disease (NAFLD) is the most common liver disease in the USA and may be present in up to 20% of the general population. A subset of patients with NAFLD has non-alcoholic steatohepatitis (NASH), a more severe form of this disease associated with hepatocellular injury, inflammation and varying levels of fibrosis. Patients with NASH are at increased risk of progression to cirrhosis and end-stage liver disease. Thus, there is an urgent need to understand the mechanisms whereby patients with NAFLD develop NASH. The two-hit hypothesis suggests that the primary insult in NAFLD is insulin resistance and increased circulating free fatty acid levels and that NASH may develop in the presence of a second hit leading to increased oxidative stress in the liver. A large body of laboratory and clinical data suggests that hepatic iron overload is associated with production of reactive oxygen species, and may lead to increased liver injury and hepatic fibrogenesis via induction of a number of pathways, many of which involve the redox-sensitive nuclear factor-κB (NF-κB). In a preliminary study of >800 subjects enrolled in the NASH Clinical Research Network (CRN), we have found that hepatic iron deposition is present in 35% of patients and that the presence and pattern of hepatic iron deposition is associated with NASH and advanced fibrosis. Hepcidin, a recently described circulating peptide has been identified as a key regulator of iron absorption and is shown to be regulated by the HFE, TFR2, or SMAD4/BMP/HJV pathway. Recent studies have also identified that hepcidin expression may be regulated via an inflammatory pathway involving IL6/JAK/STAT3. We propose the novel hypothesis that the degree and pattern of iron deposition in the liver in NASH patients reflects this dual regulation of hepcidin expression; increased circulating hepcidin level, possibly from visceral fat stores, may contribute to iron loading in hepatic reticuloendothelial cells (REC) resulting in necroinflammation, activation of pro-inflammatory cytokines and fibrogenesis. By contrast, hepatocellular iron deposition may be associated with downregulation of hepcidin expression due to polymorphisms in genes involved in iron regulation or dietary iron or alcohol consumption. The proposed studies will provide definitive information about the role of iron and iron modifying genes in the pathogenesis of NASH. They will also explore the association between iron loading in hepatic REC, gene expression of NF-κB in the liver and activity of TNF-α, IL- 6, IL-8 and TGF-β. The proposed studies are feasible, will harness the vast resources of the NASH CRN and thus will be an ideal Ancillary Study to the NASH CRN.

Public Health Relevance

NAFLD is the most common liver disease in Western societies. It is estimated that about 6 million Americans are at risk of developing cirrhosis from NAFLD. We have identified that greater than one third of patients with NAFLD have hepatic iron deposition which is associated with progression to more severe disease in most cases. The goal of this study is to determine the mechanisms leading to hepatic iron deposition and the how iron causes worsened NAFLD severity.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
High Priority, Short Term Project Award (R56)
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Special Emphasis Panel (ZDK1-GRB-7 (J2))
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Doo, Edward
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Benaroya Research Institute at Virginia Mason
United States
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Maliken, Bryan D; Nelson, James E; Klintworth, Heather M et al. (2013) Hepatic reticuloendothelial system cell iron deposition is associated with increased apoptosis in nonalcoholic fatty liver disease. Hepatology 57:1806-13
Kowdley, Kris V; Belt, Patricia; Wilson, Laura A et al. (2012) Serum ferritin is an independent predictor of histologic severity and advanced fibrosis in patients with nonalcoholic fatty liver disease. Hepatology 55:77-85
Nelson, James E; Brunt, Elizabeth M; Kowdley, Kris V et al. (2012) Lower serum hepcidin and greater parenchymal iron in nonalcoholic fatty liver disease patients with C282Y HFE mutations. Hepatology 56:1730-40
Maliken, Bryan D; Nelson, James E; Kowdley, Kris V (2011) The hepcidin circuits act: balancing iron and inflammation. Hepatology 53:1764-6