Autoimmune, Cholestatic and Biliary Disease
Article first published online: 4 DEC 2012
Copyright © 2012 American Association for the Study of Liver Diseases
Volume 56, Issue 6, pages 2288–2296, December 2012
How to Cite
Xia, X., Jung, D., Webb, P., Zhang, A., Zhang, B., Li, L., Ayers, S. D., Gabbi, C., Ueno, Y., Gustafsson, J.-Å., Alpini, G., Moore, D. D. and LeSage, G. D. (2012), Liver X receptor β and peroxisome proliferator-activated receptor δ regulate cholesterol transport in murine cholangiocytes. Hepatology, 56: 2288–2296. doi: 10.1002/hep.25919
Potential conflict of interest: Nothing to report.
Supported by National Institutes of Health grants R01 DK53366 (to D. D. M.), RC4 DK90849 (to P. W.), and R01 DK54208 (to G. D. L.), and R01 DK062975 and a VA Merit Award (to G. A.).
- Issue published online: 4 DEC 2012
- Article first published online: 4 DEC 2012
- Accepted manuscript online: 22 JUN 2012 08:46AM EST
- Manuscript Accepted: 3 JUN 2012
- Manuscript Received: 11 JAN 2012
- National Institutes of Health. Grant Numbers: R01 DK53366 (to D. D. M.), RC4 DK90849 (to P. W.), R01 DK54208 (to G. D. L.), R01 DK062975
Nuclear receptors (NRs) play crucial roles in the regulation of hepatic cholesterol synthesis, metabolism, and conversion to bile acids, but their actions in cholangiocytes have not been examined. In this study, we investigated the roles of NRs in cholangiocyte physiology and cholesterol metabolism and flux. We examined the expression of NRs and other genes involved in cholesterol homeostasis in freshly isolated and cultured murine cholangiocytes and found that these cells express a specific subset of NRs, including liver X receptor (LXR) β and peroxisome proliferator-activated receptor (PPAR) δ. Activation of LXRβ and/or PPARδ in cholangiocytes induces ATP-binding cassette cholesterol transporter A1 (ABCA1) and increases cholesterol export at the basolateral compartment in polarized cultured cholangiocytes. In addition, PPARδ induces Niemann-Pick C1-like L1 (NPC1L1), which imports cholesterol into cholangiocytes and is expressed on the apical cholangiocyte membrane via specific interaction with a peroxisome proliferator-activated response element (PPRE) within the NPC1L1 promoter. Conclusion: We propose that (1) LXRβ and PPARδ coordinate NPC1L1/ABCA1-dependent vectorial cholesterol flux from bile through cholangiocytes and (2) manipulation of these processes may influence bile composition with important applications in cholestatic liver disease and gallstone disease, two serious health concerns for humans. (HEPATOLOGY 2012;56:2288–2296)