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Liver X receptor β and peroxisome proliferator‐activated receptor δ regulate cholesterol transport in murine cholangiocytes
Author(s) -
Xia Xuefeng,
Jung Dongju,
Webb Paul,
Zhang Aijun,
Zhang Bin,
Li Lifei,
Ayers Stephen D.,
Gabbi Chiara,
Ueno Yoshiyuki,
Gustafsson JanÅke,
Alpini Gianfranco,
Moore David D.,
LeSage Gene D.
Publication year - 2012
Publication title -
hepatology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.488
H-Index - 361
eISSN - 1527-3350
pISSN - 0270-9139
DOI - 10.1002/hep.25919
Subject(s) - liver x receptor , peroxisome proliferator activated receptor , cholangiocyte , liver receptor homolog 1 , abca1 , peroxisome , nuclear receptor , microbiology and biotechnology , cholesterol , biology , medicine , reverse cholesterol transport , endocrinology , liver x receptor alpha , receptor , fatty liver , lipid metabolism , biochemistry , transporter , transcription factor , lipoprotein , disease , gene
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. (H EPATOLOGY 2012;56:2288–2296)