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

Background & Aims: Retinoid X Receptor a (RXRa) 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 RXRa 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 RXRa lacking the DNA-Binding-Domain (hsRxraDex4), 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 hsRxaDex4 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-RxraDex4 mice compared to WT mice, but not in DDC-fed hs-RxraDex4 mice. Increased necrosis and inflammation was observed in CA-fed, but not in DDC-fed hsRxraDex4 mice. Apoptotic markers DR5, CK8, CK18 RNA were increased in CA-and DDC-fed hs-RxraDex4 mice. Cleaved caspase 3, CK18 and p-JNK protein were elevated in CA-fed but not in DDC-fed hs-RxraDex4 mice. Induction of Ostb and Cyp2b10 RNA was impaired in CA-fed and DDC-fed hs-RxraDex4 mice. Surprisingly, DDC-fed hs-RxraDex4 mice showed attenuated fibrosis compared to DDC-fed WT mice. Conclusions: These two models of cholestasis identify common and injury-specific roles for RXRa heterodimers and the functional relevance of an intact RXRa-DBD in the hepatocytic adaptive cholestatic response. (C) 2013 European Association for the Study of the Liver. Published by Elsevier B. V. All rights reserved.