title: Gene-specific alterations of hepatic gene expression by ligand activation or hepatocyte-selective inhibition of retinoid X receptor-α signalling during inflammation.
abstract: BACKGROUND
  Inflammation leads to transcriptional downregulation of many hepatic genes, particularly those activated by retinoid X receptor-α (RXRα) heterodimers. Inflammation-mediated reduction of nuclear RXRα levels is a main factor in reduced nuclear receptor (NR)-regulated hepatic gene expression, eventually leading to cholestasis and liver damage.
  
  
  OBJECTIVE
  To investigate roles for RXRα in hepatic gene expression during inflammation, using two complementary mouse models: ligand activation of RXRα, and in mice expressing hepatocyte-specific expression of RXRα missing its DNA-binding domain (DBD; hs-RxrαΔex4(-/-) ).
  
  
  METHODS
  To activate RXRα, mice were gavage-fed with LG268 or vehicle for 5 days. To inhibit RXRα function, hs-RxrαΔex4(-/-) mice were used. All mice were injected intraperitoneally with lipopolysaccharides (LPS) or saline for 16 h prior to analysis of hepatic RNA, protein and NR-DNA binding.
  
  
  RESULTS
  LG268 treatment attenuated the LPS-mediated reductions of several RXRα-regulated genes, coinciding with maintained RXRα occupancy in both Bsep and Ostβ promoters. Lacking full hepatocyte RXRα function (hs-RxrαΔex4(-/-) mice) led to enhancement of LPS-mediated changes in gene expression, but surprisingly, maintenance of RNA levels of some RXRα-regulated genes. Investigations revealed that hs-RxrαΔex4(-/-) hepatocytes expressed an internally truncated, approximately 44 kDa, RXRα-form. DNA-binding capacity of NR heterodimers was equivalent in wild-type and hs-RxrαΔex4(-/-) livers, but reduced by LPS in both. Chromatin immunoprecipitation quantitative PCR revealed that RXRα occupancy to the Bsep RXRα:Farnesoid X Receptor site was reduced, but not absent, in hs-RxrαΔex4(-/-) livers.
  
  
  CONCLUSIONS
  There are differential regulatory roles for hepatic RXRα, both in basal and inflammatory states, suggesting new and complex multidomain roles for RXRα in regulating hepatic gene expression. Moreover, there is an unexpected non-obligate role for the DBD of RXRα.
authors.affiliation: Department of Pediatrics, Texas Children's Liver Center, Baylor College of Medicine, Houston, TX, USA.
authors.forename: Astrid
authors.initials: A
authors.lastname: Kosters
authors.forename: Feng
authors.initials: F
authors.lastname: Tian
authors.forename: Yu-Jui Yvonne
authors.initials: YJ
authors.lastname: Wan
authors.forename: Yvonne Yu-Jie
authors.initials: YY
authors.lastname: Wan
authors.forename: Saul J
authors.initials: SJ
authors.lastname: Karpen
mesh_terms: D000818:Animals; D002467:Cell Nucleus / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D004195:Disease Models, Animal; D015870:Gene Expression / Q000187:drug effects*; D022781:Hepatocytes / Q000378:metabolism*; D007249:Inflammation / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D008024:Ligands; D008070:Lipopolysaccharides / Q000494:pharmacology; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009930:Organic Chemicals / Q000494:pharmacology; D047490:Retinoid X Receptor alpha / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects
chemical_list: C423914:LG 268; D008024:Ligands; D008070:Lipopolysaccharides; D009930:Organic Chemicals; D047490:Retinoid X Receptor alpha
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