Liver X receptor β and peroxisome proliferator-activated receptor δ regulate cholesterol transport in murine cholangiocytes

Xuefeng Xia, Dongju Jung, Paul Webb, Aijun Zhang, Bin Zhang, Lifei Li, Stephen D. Ayers, Chiara Gabbi, Yoshiyuki Ueno, Jan Åke Gustafsson, Gianfranco Alpini, David D. Moore, Gene D. Lesage

Research output: Contribution to journalArticle

30 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)2288-2296
Number of pages9
JournalHepatology
Volume56
Issue number6
DOIs
StatePublished - Dec 2012

ASJC Scopus subject areas

  • Hepatology

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