| First Author | Kosters A | Year | 2014 |
| Journal | J Hepatol | Volume | 60 |
| Issue | 2 | Pages | 362-9 |
| PubMed ID | 24120911 | Mgi Jnum | J:273469 |
| Mgi Id | MGI:6276818 | Doi | 10.1016/j.jhep.2013.09.026 |
| Citation | Kosters A, et al. (2014) Impaired bile acid handling and aggravated liver injury in mice expressing a hepatocyte-specific RXRalpha variant lacking the DNA-binding domain. J Hepatol 60(2):362-9 |
| abstractText | BACKGROUND & AIMS: Retinoid X Receptor alpha (RXRalpha) 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 RXRalpha 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 RXRalpha lacking the DNA-Binding-Domain (hs-RxralphaDeltaex4(-/-)), 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-RxalphaDeltaex4(-/-) 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-RxralphaDeltaex4(-/-) mice compared to WT mice, but not in DDC-fed hs-RxralphaDeltaex4(-/-) mice. Increased necrosis and inflammation was observed in CA-fed, but not in DDC-fed hs-RxralphaDeltaex4(-/-) mice. Apoptotic markers DR5, CK8, CK18 RNA were increased in CA- and DDC-fed hs-RxralphaDeltaex4(-/-) mice. Cleaved caspase 3, CK18 and p-JNK protein were elevated in CA-fed but not in DDC-fed hs-RxralphaDeltaex4(-/-) mice. Induction of Ostbeta and Cyp2b10 RNA was impaired in CA-fed and DDC-fed hs-RxralphaDeltaex4(-/-) mice. Surprisingly, DDC-fed hs-RxralphaDeltaex4(-/-) mice showed attenuated fibrosis compared to DDC-fed WT mice. CONCLUSIONS: These two models of cholestasis identify common and injury-specific roles for RXRalpha heterodimers and the functional relevance of an intact RXRalpha-DBD in the hepatocytic adaptive cholestatic response. |
