title: Impaired bile acid handling and aggravated liver injury in mice expressing a hepatocyte-specific RXRα variant lacking the DNA-binding domain.
abstract: OBJECTIVE
  Retinoid X Receptor α (RXRα) is the principal heterodimerization partner of class II Nuclear Receptors (NRs), and a major regulator of gene expression of numerous hepatic processes, including bile acid (BA) homeostasis through multiple partners. Specific contributions of hepatic RXRα domains in heterodimer function in response to either BA load or ductular cholestasis are not fully characterized.
  
  
  METHODS
  Wild-type (WT) mice and mice expressing a hepatocyte-specific RXRα lacking the DNA-Binding-Domain (hs-RxrαΔex4(-/-)), which retains partial ability to heterodimerize with its partners, were fed a 1% cholic acid (CA) diet for 5 days, a 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC) diet for 3 weeks, or control diet.
  
  
  RESULTS
  Serum ALT (6.5-fold; p<0.05), AST (9.3-fold; p=0.06) and BA (2.8-fold; p<0.05) were increased in CA-fed hs-RxαΔex4(-/-) mice compared to CA-fed WT mice, but were equally induced between genotypes by DDC-feeding. CA-feeding elevated total (4.4-fold; p=0.06) and unconjugated (2.2-fold; p<0.02) bilirubin levels in hs-RxrαΔex4(-/-) mice compared to WT mice, but not in DDC-fed hs-RxrαΔex4(-/-) mice. Increased necrosis and inflammation was observed in CA-fed, but not in DDC-fed hs-RxrαΔex4(-/-) mice. Apoptotic markers DR5, CK8, CK18 RNA were increased in CA- and DDC-fed hs-RxrαΔex4(-/-) mice. Cleaved caspase 3, CK18 and p-JNK protein were elevated in CA-fed but not in DDC-fed hs-RxrαΔex4(-/-) mice. Induction of Ostβ and Cyp2b10 RNA was impaired in CA-fed and DDC-fed hs-RxrαΔex4(-/-) mice. Surprisingly, DDC-fed hs-RxrαΔex4(-/-) mice showed attenuated fibrosis compared to DDC-fed WT mice.
  
  
  CONCLUSIONS
  These two models of cholestasis identify common and injury-specific roles for RXRα heterodimers and the functional relevance of an intact RXRα-DBD in the hepatocytic adaptive cholestatic response.
authors.affiliation: Division of Gastroenterology, Hepatology, and Nutrition, Department of Pediatrics, Emory University School of Medicine, Atlanta, GA 30322, United States.
authors.forename: Astrid
authors.initials: A
authors.lastname: Kosters
authors.affiliation: Division of Gastroenterology, Hepatology, and Nutrition, Department of Pediatrics, Baylor College of Medicine, Houston, TX 77030, United States.
authors.forename: Julio C
authors.initials: JC
authors.lastname: Felix
authors.affiliation: Division of Critical Care Medicine, Department of Pediatrics, Baylor College of Medicine, Houston, TX 77030, United States.
authors.forename: Moreshwar S
authors.initials: MS
authors.lastname: Desai
authors.affiliation: Division of Gastroenterology, Hepatology, and Nutrition, Department of Pediatrics, Emory University School of Medicine, Atlanta, GA 30322, United States. Electronic address: skarpen@emory.edu.
authors.forename: Saul J
authors.initials: SJ
authors.lastname: Karpen
mesh_terms: D000818:Animals; D017209:Apoptosis; D001647:Bile Acids and Salts / Q000378:metabolism*; D002779:Cholestasis / Q000209:etiology / Q000235:genetics / Q000378:metabolism; D019826:Cholic Acid / Q000008:administration & dosage; D015870:Gene Expression; D022781:Hepatocytes / Q000378:metabolism; D008099:Liver / Q000293:injuries* / Q000378:metabolism* / Q000473:pathology; D008297:Male; D051379:Mice; D057507:Mice, 129 Strain; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA; D018345:Mice, Knockout; D008817:Mice, Mutant Strains; D050505:Mutant Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D010446:Peptide Fragments / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D017434:Protein Structure, Tertiary; D011725:Pyridines / Q000008:administration & dosage / Q000633:toxicity; D047490:Retinoid X Receptor alpha / Q000172:deficiency / Q000235:genetics* / Q000378:metabolism*
chemical_list: C530773:3,5-diethoxycarbonyl-1,4-dihydrocollidine; D001647:Bile Acids and Salts; D050505:Mutant Proteins; D010446:Peptide Fragments; D011725:Pyridines; D047490:Retinoid X Receptor alpha; D019826:Cholic Acid
keywords: Apoptosis; BA; Bile acids; Biliary fibrosis; CA; DBD; DDC; DNA-Binding Domain; Liver injury; NR; Nuclear Receptors; Nuclear receptors; RXRα; Retinoid X Receptor α; Retinoid x receptor; bile acids; cholic acid