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Genetic Resistance to Liver Fibrosis on A/J Mouse Chromosome 17
Author(s) -
DeSantis David A.,
Lee Peter,
Doerner Stephanie K.,
Ko ChihWei,
Kawasoe Jean H.,
HillBaskin Annie E.,
Ernest Sheila R.,
Bhargava Prerna,
Hur Kyu Yeon,
Cresci Gail A.,
Pritchard Michele T.,
Lee ChihHao,
Nagy Laura E.,
Nadeau Joseph H.,
Croniger Colleen M.
Publication year - 2013
Publication title -
alcoholism: clinical and experimental research
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.267
H-Index - 153
eISSN - 1530-0277
pISSN - 0145-6008
DOI - 10.1111/acer.12157
Subject(s) - quantitative trait locus , biology , steatohepatitis , congenic , candidate gene , steatosis , single nucleotide polymorphism , genetics , fibrosis , hepatic fibrosis , fatty liver , microbiology and biotechnology , gene , medicine , endocrinology , genotype , disease
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 C 57 BL /6 J (B6) genetic background. Previously, we identified quantitative trait loci ( QTL s) 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 QTL s conferred resistance to alcohol‐induced liver injury and fibrosis, B 6, A / J , CSS ‐17, and congenics 17 C ‐1 and 17 C ‐6 were either fed L ieber– D e C arli ethanol ( E t OH )‐containing diet or had carbon tetrachloride ( CC l 4 ) 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 B 6 and A / J strains, we identified candidate genes in Obrq13 and Obrq15 that contained single‐nucleotide polymorphisms ( SNP s) 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 E t OH diet study and after CC l 4 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 CSS s, we identified 2 candidate genes, Noxo1 and Nlrc4 , which modulate genetic susceptibility in ASH .