title: Genetic dissection of the fatty liver QTL Fl1sa by using congenic mice and identification of candidate genes in the liver and epididymal fat.
abstract: Nonalcoholic fatty liver disease (NAFLD) is a multifactorial disease caused by interactions between environmental and genetic factors. The SMXA-5 mouse is a high-fat diet-induced fatty liver model established from SM/J and A/J strains. We have previously identified Fl1sa, a quantitative trait locus (QTL) for fatty liver on chromosome 12 (centromere-53.06 Mb) of SMXA-5 mice. However, the chromosomal region containing Fl1sa was too broad. The aim of this study was to narrow the Fl1sa region by genetic dissection using novel congenic mice and to identify candidate genes within the narrowed Fl1sa region.
  
  
  
  We established two congenic strains, R2 and R3, from parental A/J-12SMand A/J strains. R2 and R3 strains have genomic intervals of centromere-29.20 Mb and 29.20-46.75 Mb of chromosome 12 derived from SM/J, respectively. Liver triglyceride content in R2 and R3 mice was significantly lower than that in A/J mice fed with a high-fat diet for 7 weeks. This result suggests that at least one of the genes responsible for fatty liver exists within the two chromosomal regions centromere-29.20 Mb (R2) and 29.20-46.75 Mb (R3). We found that liver triglyceride accumulation is inversely correlated with epididymal fat weight among the parental and congenic strains. Therefore, the ectopic fat accumulation in the liver may be due to organ-organ interactions between the liver and epididymal fat. To identify candidate genes in Fl1sa, we performed a DNA microarray analysis using the liver and epididymal fat in A/J and A/J-12SMmice fed with a high-fat diet for 7 weeks. In epididymal fat, mRNA levels of Zfp125 (in R2) and Nrcam (in R3) were significantly different in A/J-12SMmice from those in A/J mice. In the liver, mRNA levels of Iah1 (in R2) and Rrm2 (in R2) were significantly different in A/J-12SMmice from those in A/J mice.
  
  
  
  In this study, using congenic mice analysis, we narrowed the chromosomal region containing Fl1sa to two regions of mouse chromosome 12. We then identified 4 candidate genes in Fl1sa: Iah1 and Rrm2 from the liver and Zfp125 and Nrcam from epididymal fat.
authors.affiliation: Department of Applied Molecular Biosciences, Graduate School of Bioagricultural Sciences, Nagoya University, Nagoya, 464-8601, Japan.
authors.forename: Miyako
authors.initials: M
authors.lastname: Suzuki
authors.affiliation: Department of Applied Molecular Biosciences, Graduate School of Bioagricultural Sciences, Nagoya University, Nagoya, 464-8601, Japan. misatok@agr.nagoya-u.ac.jp.
authors.forename: Misato
authors.initials: M
authors.lastname: Kobayashi
authors.affiliation: Division of Experimental Animals, Center for Promotion of Medical Research and Education, Graduate School of Medicine, Nagoya University, Nagoya, 466-8550, Japan.
authors.forename: Tamio
authors.initials: T
authors.lastname: Ohno
authors.affiliation: Department of Applied Molecular Biosciences, Graduate School of Bioagricultural Sciences, Nagoya University, Nagoya, 464-8601, Japan.
authors.forename: Shinsaku
authors.initials: S
authors.lastname: Kanamori
authors.affiliation: Department of Applied Molecular Biosciences, Graduate School of Bioagricultural Sciences, Nagoya University, Nagoya, 464-8601, Japan.
authors.forename: Soushi
authors.initials: S
authors.lastname: Tateishi
authors.affiliation: Department of Applied Molecular Biosciences, Graduate School of Bioagricultural Sciences, Nagoya University, Nagoya, 464-8601, Japan.
authors.forename: Atsushi
authors.initials: A
authors.lastname: Murai
authors.affiliation: Department of Applied Molecular Biosciences, Graduate School of Bioagricultural Sciences, Nagoya University, Nagoya, 464-8601, Japan.
authors.forename: Fumihiko
authors.initials: F
authors.lastname: Horio
mesh_terms: D000273:Adipose Tissue; D000818:Animals; D015415:Biomarkers; D059305:Diet, High-Fat; D004822:Epididymis; D005234:Fatty Liver / Q000097:blood / Q000235:genetics* / Q000473:pathology; D015870:Gene Expression; D020869:Gene Expression Profiling; D056726:Genetic Association Studies; D008099:Liver; D008297:Male; D051379:Mice; D020297:Mice, Congenic; D010641:Phenotype; D040641:Quantitative Trait Loci; D019655:Quantitative Trait, Heritable; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism
chemical_list: D015415:Biomarkers; D012333:RNA, Messenger
keywords: Candidate gene; Congenic; Epididymal fat; Fatty liver; Interaction; Mouse; QTL; fl1sa