Impaired bile acid handling and aggravated liver injury in mice expressing a hepatocyte-specific RXRα variant lacking the DNA-binding domain

J Hepatol. 2014 Feb;60(2):362-9. doi: 10.1016/j.jhep.2013.09.026. Epub 2013 Oct 10.

Abstract

Background & aims: 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.

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.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Apoptosis
  • Bile Acids and Salts / metabolism*
  • Cholestasis / etiology
  • Cholestasis / genetics
  • Cholestasis / metabolism
  • Cholic Acid / administration & dosage
  • Gene Expression
  • Hepatocytes / metabolism
  • Liver / injuries*
  • Liver / metabolism*
  • Liver / pathology
  • Male
  • Mice
  • Mice, 129 Strain
  • Mice, Inbred C57BL
  • Mice, Inbred DBA
  • Mice, Knockout
  • Mice, Mutant Strains
  • Mutant Proteins / chemistry
  • Mutant Proteins / genetics
  • Mutant Proteins / metabolism
  • Peptide Fragments / chemistry
  • Peptide Fragments / genetics
  • Peptide Fragments / metabolism
  • Protein Structure, Tertiary
  • Pyridines / administration & dosage
  • Pyridines / toxicity
  • Retinoid X Receptor alpha / deficiency
  • Retinoid X Receptor alpha / genetics*
  • Retinoid X Receptor alpha / metabolism*

Substances

  • 3,5-diethoxycarbonyl-1,4-dihydrocollidine
  • Bile Acids and Salts
  • Mutant Proteins
  • Peptide Fragments
  • Pyridines
  • Retinoid X Receptor alpha
  • Cholic Acid