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


CONCLUSIONS
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.
Methodist Hospital Research Institute, Weill Cornell School of Medicine, Houston, TX 77030, USA. xxia2@tmhs.org
Xuefeng
X
Xia
Dongju
D
Jung
Paul
P
Webb
Aijun
A
Zhang
Bin
B
Zhang
Lifei
L
Li
Stephen D
SD
Ayers
Chiara
C
Gabbi
Yoshiyuki
Y
Ueno
Jan-Åke
JÅ
Gustafsson
Gianfranco
G
Alpini
David D
DD
Moore
Gene D
GD
Lesage
D064286:ATP Binding Cassette Transporter 1; D018528:ATP-Binding Cassette Transporters / Q000378:metabolism; D000818:Animals; D001652:Bile Ducts / Q000166:cytology / Q000378:metabolism; D002478:Cells, Cultured; D002784:Cholesterol / Q000378:metabolism*; D020869:Gene Expression Profiling; D051557:Hepatocyte Nuclear Factor 4 / Q000235:genetics / Q000378:metabolism; D022781:Hepatocytes / Q000378:metabolism; D006706:Homeostasis / Q000235:genetics; D000071518:Liver X Receptors; D026901:Membrane Transport Proteins / Q000378:metabolism; D057093:Orphan Nuclear Receptors / Q000235:genetics* / Q000378:metabolism*; D047494:PPAR delta / Q000235:genetics* / Q000378:metabolism*; D047495:PPAR gamma / Q000235:genetics / Q000378:metabolism; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D000077297:Pregnane X Receptor; D016601:RNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D051381:Rats; D018167:Receptors, Calcitriol / Q000235:genetics / Q000378:metabolism; D011960:Receptors, Estrogen / Q000235:genetics / Q000378:metabolism; D011987:Receptors, Steroid / Q000235:genetics / Q000378:metabolism; D011988:Receptors, Thyroid Hormone / Q000235:genetics / Q000378:metabolism; D047488:Retinoid X Receptors / Q000235:genetics / Q000378:metabolism; D013250:Steroid Hydroxylases / Q000235:genetics / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism
C577836:ABCA1 protein, human; D064286:ATP Binding Cassette Transporter 1; D018528:ATP-Binding Cassette Transporters; D051557:Hepatocyte Nuclear Factor 4; C496594:Hnf4a protein, rat; D000071518:Liver X Receptors; D026901:Membrane Transport Proteins; C482445:Npc1l1 protein, mouse; D057093:Orphan Nuclear Receptors; D047494:PPAR delta; D047495:PPAR gamma; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; C501429:Ppargc1a protein, rat; D000077297:Pregnane X Receptor; D016601:RNA-Binding Proteins; D018167:Receptors, Calcitriol; D011960:Receptors, Estrogen; D011987:Receptors, Steroid; D011988:Receptors, Thyroid Hormone; D047488:Retinoid X Receptors; D014157:Transcription Factors; D002784:Cholesterol; D013250:Steroid Hydroxylases