title: Deletion of exons 3 and 4 in the mouse Nr1d1 gene worsens high-fat diet-induced hepatic steatosis.
abstract: OBJECTIVE
  To elucidate the role of nuclear receptor subfamily 1, group D, member 1 (Nr1d1) in hepatic lipid metabolism and pathogenesis of nonalcoholic fatty liver diseases, Nr1d1 gene mutant mice, in which the DNA-binding domain (exons 3 and 4) was deleted (Nr1d1 Δex3/4), were challenged with a high-fat diet (HFD), and the gene expression patterns that responded to this alteration were profiled.
  
  
  METHODS
  The Nr1d1 Δex3/4 mice were fed an HFD for 12weeks. Liver tissues were examined by histology, and lipid droplets were detected by Oil-Red O staining. Serum biochemical analyses were performed to assess markers of liver injury. Microarray analysis was used to profile hepatic gene expression patterns. Functional annotation, upstream prediction, and gene coexpression prediction analyses were performed.
  
  
  RESULTS
  The Nr1d1 Δex3/4 mice showed enhanced hepatic steatosis after being challenged with an HFD, but not with a low-fat diet, indicating an interaction between diet and genotype for this phenotypic change. Gene expression profiling revealed that this interaction might involve neutrophil recruitment and the cyclic adenosine monophosphate metabolic pathway. A study of transcription factor binding site enrichment suggested that CCAAT/enhancer-binding protein alpha and hepatocyte nuclear factor 4 alpha were associated with this phenotypic change.
  
  
  CONCLUSIONS
  Loss of DNA binding of Nr1d1 was associated with a deterioration in hepatic steatosis. The interaction between the Nr1d1 Δex3/4 genotype with an HFD might mediate these phenotypic changes, probably through a nonclassical transcriptional function of Nr1d1.
authors.affiliation: College of Pharmacy and Bio-MAX/N-Bio, Seoul National University, Seoul 08826, Republic of Korea.
authors.forename: Hyelin
authors.initials: H
authors.lastname: Na
authors.affiliation: Research Institute, Graduate School of Cancer Science and Policy, National Cancer Center, Gyeonggi-do 10408, Republic of Korea.
authors.forename: Ho
authors.initials: H
authors.lastname: Lee
authors.affiliation: College of Pharmacy and Bio-MAX/N-Bio, Seoul National University, Seoul 08826, Republic of Korea.
authors.forename: Min-Ho
authors.initials: MH
authors.lastname: Lee
authors.affiliation: Research Institute, Graduate School of Cancer Science and Policy, National Cancer Center, Gyeonggi-do 10408, Republic of Korea.
authors.forename: Han Jeong
authors.initials: HJ
authors.lastname: Lim
authors.affiliation: College of Pharmacy and Bio-MAX/N-Bio, Seoul National University, Seoul 08826, Republic of Korea.
authors.forename: Hyeon-Ji
authors.initials: HJ
authors.lastname: Kim
authors.affiliation: Research Institute, Graduate School of Cancer Science and Policy, National Cancer Center, Gyeonggi-do 10408, Republic of Korea.
authors.forename: Yoon
authors.initials: Y
authors.lastname: Jeon
authors.affiliation: College of Pharmacy and Bio-MAX/N-Bio, Seoul National University, Seoul 08826, Republic of Korea.
authors.forename: Hae-Lim
authors.initials: HL
authors.lastname: Kang
authors.affiliation: College of Pharmacy and Bio-MAX/N-Bio, Seoul National University, Seoul 08826, Republic of Korea. Electronic address: molee@snu.ac.kr.
authors.forename: Mi-Ock
authors.initials: MO
authors.lastname: Lee
mesh_terms: D000818:Animals; D059305:Diet, High-Fat / Q000009:adverse effects; D005091:Exons; D005260:Female; D017353:Gene Deletion; D050356:Lipid Metabolism; D008099:Liver / Q000378:metabolism / Q000473:pathology*; D051379:Mice; D008810:Mice, Inbred C57BL; D041681:NIH 3T3 Cells; D065626:Non-alcoholic Fatty Liver Disease / Q000209:etiology / Q000235:genetics* / Q000378:metabolism / Q000473:pathology*; D056953:Nuclear Receptor Subfamily 1, Group D, Member 1 / Q000235:genetics*; D059467:Transcriptome
chemical_list: C498262:Nr1d1 protein, mouse; D056953:Nuclear Receptor Subfamily 1, Group D, Member 1
keywords: Cebpα; Hnf4α; Lipid metabolism; Liver; Nr1d1; Thrsp