title: Differences in hepatic expression of iron, inflammation and stress-related genes in patients with nonalcoholic steatohepatitis.
abstract: Nonalcoholic fatty liver disease (NAFLD) is the most common cause of chronic liver disease worldwide. We have previously shown that hepatic reticuloendothelial system (RES) iron deposition is associated with an advanced degree of nonalcoholic steatohepatitis (NASH) in humans. In this study, we aimed to determine differentially expressed genes related to iron overload, inflammation and oxidative stress pathways, with the goal of identifying factors associated with NASH progression. Seventy five patients with NAFLD were evaluated for their biochemical parameters and their liver tissue analyzed for NASH histological characteristics. Gene expression analysis of pathways related to iron homeostasis, inflammation and oxidative stress was performed using real-time PCR. Gene expression was compared between subjects based on disease status and presence of hepatic iron staining. We observed increased gene expression of hepcidin (HAMP) (2.3 fold, p = 0.027), transmembrane serine proteinase 6 (TMPRSS6) (8.4 fold, p = 0.003), signal transducer and activator of transcription 3 (STAT3) (5.5 fold, p = 0.004), proinflammatory cytokines; IL-1? (2.7 fold, p = 0.046) and TNF-? (3.8 fold, p = 0.001) in patients with NASH. TMPRSS6, a negative regulator of HAMP, is overexpressed in patients with NASH and HIF1? (hypoxia inducible factor-1) is downregulated. NAFLD patients with hepatic iron deposition exhibited higher hepcidin expression (3.1 fold, p = 0.04) but lower expression of cytokines. In conclusion, we observed elevated hepatic HAMP expression in patients with NASH and in NAFLD patients who had hepatic iron deposition, while proinflammatory cytokines displayed elevated expression only in patients with NASH, suggesting a regulatory role for hepcidin in NAFL to NASH transition and in mitigating inflammatory responses.
authors.affiliation: Organ Care Research and Liver Care Network, Swedish Medical Center, Seattle WA.
authors.forename: Priya
authors.initials: P
authors.lastname: Handa
authors.affiliation: Organ Care Research and Liver Care Network, Swedish Medical Center, Seattle WA.
authors.forename: Akhila L
authors.initials: AL
authors.lastname: Vemulakonda
authors.affiliation: Benaroya Research Institute Seattle WA.
authors.forename: Bryan D
authors.initials: BD
authors.lastname: Maliken
authors.affiliation: rgan Care Research and Liver Care Network, Swedish Medical Center, Seattle WA.
authors.forename: Vicki
authors.initials: V
authors.lastname: Morgan-Stevenson
authors.affiliation: Benaroya Research Institute Seattle WA.
authors.forename: James E
authors.initials: JE
authors.lastname: Nelson
authors.affiliation: Benaroya Research Institute Seattle WA.
authors.forename: Barjinder K
authors.initials: BK
authors.lastname: Dhillon
authors.affiliation: Organ Care Research and Liver Care Network, Swedish Medical Center, Seattle WA.
authors.forename: Kelly A
authors.initials: KA
authors.lastname: Hennessey
authors.affiliation: Benaroya Research Institute Seattle WA.
authors.forename: Rohit
authors.initials: R
authors.lastname: Gupta
authors.affiliation: University of Washington Medical Center, Seattle WA.
authors.forename: Matthew M
authors.initials: MM
authors.lastname: Yeh
authors.affiliation: Organ Care Research and Liver Care Network, Swedish Medical Center, Seattle WA.
authors.forename: Kris V
authors.initials: KV
authors.lastname: Kowdley
mesh_terms: D000328:Adult; D005260:Female; D005786:Gene Expression Regulation; D064451:Hepcidins / Q000235:genetics; D006801:Humans; D007249:Inflammation / Q000097:blood / Q000175:diagnosis / Q000235:genetics*; D018836:Inflammation Mediators / Q000097:blood; D053583:Interleukin-1beta / Q000097:blood / Q000235:genetics; D007501:Iron / Q000032:analysis*; D019190:Iron Overload / Q000097:blood / Q000175:diagnosis / Q000235:genetics*; D008099:Liver / Q000737:chemistry* / Q000473:pathology; D008297:Male; D008565:Membrane Proteins / Q000235:genetics; D008875:Middle Aged; D065626:Non-alcoholic Fatty Liver Disease / Q000097:blood / Q000175:diagnosis / Q000235:genetics*; D018384:Oxidative Stress / Q000235:genetics*; D060888:Real-Time Polymerase Chain Reaction; D050796:STAT3 Transcription Factor / Q000235:genetics; D012697:Serine Endopeptidases / Q000235:genetics; D014409:Tumor Necrosis Factor-alpha / Q000097:blood / Q000235:genetics
chemical_list: C578702:HAMP protein, human; D064451:Hepcidins; C508585:IL1B protein, human; D018836:Inflammation Mediators; D053583:Interleukin-1beta; D008565:Membrane Proteins; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; D014409:Tumor Necrosis Factor-alpha; D007501:Iron; D012697:Serine Endopeptidases; C504318:TMPRSS6 protein, human