title: Genetic resistance to liver fibrosis on A/J mouse chromosome 17.
abstract: BACKGROUND
  Because the histological and biochemical progression of liver disease is similar in alcoholic steatohepatitis (ASH) and nonalcoholic steatohepatitis (NASH), we hypothesized that the genetic susceptibility to these liver diseases would be similar. To identify potential candidate genes that regulate the development of liver fibrosis, we studied a chromosome substitution strain (CSS-17) that contains chromosome 17 from the A/J inbred strain substituted for the corresponding chromosome on the C57BL/6J (B6) genetic background. Previously, we identified quantitative trait loci (QTLs) in CSS-17, namely obesity-resistant QTL 13 and QTL 15 (Obrq13 and Obrq15, respectively), that were associated with protection from diet-induced obesity and hepatic steatosis on a high-fat diet.
  
  
  METHODS
  To test whether these or other CSS-17 QTLs conferred resistance to alcohol-induced liver injury and fibrosis, B6, A/J, CSS-17, and congenics 17C-1 and 17C-6 were either fed Lieber-DeCarli ethanol (EtOH)-containing diet or had carbon tetrachloride (CCl4 ) administered chronically.
  
  
  RESULTS
  The congenic strain carrying Obrq15 showed resistance from alcohol-induced liver injury and liver fibrosis, whereas Obrq13 conferred susceptibility to liver fibrosis. From published deep sequencing data for chromosome 17 in the B6 and A/J strains, we identified candidate genes in Obrq13 and Obrq15 that contained single-nucleotide polymorphisms (SNPs) in the promoter region or within the gene itself. NADPH oxidase organizer 1 (Noxo1) and NLR family, CARD domain containing 4 (Nlrc4) showed altered hepatic gene expression in strains with the A/J allele at the end of the EtOH diet study and after CCl4 treatment.
  
  
  CONCLUSIONS
  Aspects of the genetics for the progression of ASH are unique compared to NASH, suggesting that the molecular mechanisms for the progression of disease are at least partially distinct. Using these CSSs, we identified 2 candidate genes, Noxo1 and Nlrc4, which modulate genetic susceptibility in ASH.
authors.affiliation: Department of Nutrition, Case Western Reserve University School of Medicine, Cleveland, Ohio.
authors.forename: David A
authors.initials: DA
authors.lastname: DeSantis
authors.forename: Peter
authors.initials: P
authors.lastname: Lee
authors.forename: Stephanie K
authors.initials: SK
authors.lastname: Doerner
authors.forename: Chih-Wei
authors.initials: CW
authors.lastname: Ko
authors.forename: Jean H
authors.initials: JH
authors.lastname: Kawasoe
authors.forename: Annie E
authors.initials: AE
authors.lastname: Hill-Baskin
authors.forename: Sheila R
authors.initials: SR
authors.lastname: Ernest
authors.forename: Prerna
authors.initials: P
authors.lastname: Bhargava
authors.forename: Kyu Yeon
authors.initials: KY
authors.lastname: Hur
authors.forename: Gail A
authors.initials: GA
authors.lastname: Cresci
authors.forename: Michele T
authors.initials: MT
authors.lastname: Pritchard
authors.forename: Chih-Hao
authors.initials: CH
authors.lastname: Lee
authors.forename: Laura E
authors.initials: LE
authors.lastname: Nagy
authors.forename: Joseph H
authors.initials: JH
authors.lastname: Nadeau
authors.forename: Colleen M
authors.initials: CM
authors.lastname: Croniger
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D051017:Apoptosis Regulatory Proteins / Q000235:genetics*; D002135:Calcium-Binding Proteins / Q000235:genetics*; D002478:Cells, Cultured; D002886:Chromosomes, Human, Pair 17 / Q000235:genetics*; D005234:Fatty Liver / Q000175:diagnosis / Q000235:genetics*; D005235:Fatty Liver, Alcoholic / Q000175:diagnosis / Q000235:genetics*; D005260:Female; D056726:Genetic Association Studies / Q000379:methods; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D006801:Humans; D051379:Mice; D020297:Mice, Congenic; D008810:Mice, Inbred C57BL; D065626:Non-alcoholic Fatty Liver Disease; D011506:Proteins / Q000235:genetics*; D040641:Quantitative Trait Loci / Q000235:genetics
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D051017:Apoptosis Regulatory Proteins; D002135:Calcium-Binding Proteins; C512299:Ipaf protein, mouse; C472287:Noxo1 protein, mouse; D011506:Proteins
keywords: A/J; C57BL/6J; CCl4; Congenic Strains; Liver Fibrosis; Nlrc4 Inflammasome