935 OVEREXPRESSION OF CREM ALPHA IN CD4+ T CELLS ACCELERATES ACUTE ConA-INDUCED HEPATITIS BUT DOES NOT INFLUENCE FIBROSIS

Abstract

Introduction: Aquaporins (AQPs) are a family of channel proteins that facilitate the osmotic movement of water and small solutes across biological membranes. In the hepatobiliary tract, AQPs participate in formation and flow of bile. We have previously shown that Liver X Receptor b (LXRb), a nuclear receptor activated by oxysterols, controls the expression of AQP-1 in pancreas and kidney. Aim and Methods: In the present study we aimed to investigate the role of LXRb in controlling water channel homeostasis in the hepatobiliary tract, in-vivo. Both male and female WT and LXRb−/− mice were studied at the age of 12 months. Results: In WT mice, LXRb protein was strongly expressed in the nuclei of intrahepatic cholangiocytes while a weak expression was detected in hepatocytes. Male LXRb−/− mice demonstrated a significant increase of serum levels of both total bilirubin and alkaline phosphatase, indicating the presence of a mild cholestasis. In the whole liver, there was a significant reduction in the levels of both the mRNA of AQP-1 and AQP-4 in male LXRb−/− mice. Interestingly, AQP-4 protein expression was detected on the plasma membrane of male WT hepatocytes while in LXRb−/− mice, the immunoreactivity was identified in the cytosol, suggesting a possible defect in its transport to the membrane. No AQP-4 was detected in female mice either WT or LXRb−/−. In the kidney, AQP-2 trafficking is controlled by caveolin-1, a major component of caveolae, that is involved in transcytosis, endocytosis and signal transduction. In prostate cancer cells, caveolin-1 is upregulated by testosterone and acts as Androgen Receptor (AR) co-regulator being involved in non-genomic effects of AR. In LXRb−/− male mice, strong immunoreactivity of caveolin-1 was detected in the cytosol while in WT mice it was on the cell surface. Thus there is impaired translocation of caveolin-1 in the mutant mice. Interestingly, in LXRb−/− male mice, serum testosterone levels were in normal range. Conclusion: LXRb regulates the level of AQP-1 and AQP-4 mRNA as well as the cellular localization of AQP-4, via caveolin-1, in male mice.