title: FXR-mediated down-regulation of CYP7A1 dominates LXRalpha in long-term cholesterol-fed NZW rabbits.
abstract: We investigated how cholesterol feeding regulates cholesterol 7alpha-hydroxylase (CYP7A1) via the nuclear receptors farnesoid X receptor (FXR) and liver X receptor alpha (LXRalpha) in New Zealand white rabbits. After 1 day of 2% cholesterol feeding, when the bile acid pool size had not expanded, mRNA levels of the FXR target genes short-heterodimer partner (SHP) and sterol 12alpha-hydroxylase (CYP8B) were unchanged, indicating that FXR activation remained constant. In contrast, the mRNA levels of the LXRalpha target genes ATP binding cassette transporter A1 (ABCA1) and cholesteryl ester transfer protein (CETP) increased 5-fold and 2.3-fold, respectively, associated with significant increases in hepatic concentrations of oxysterols. Activity and mRNA levels of CYP7A1 increased 2.4 times and 2.2 times, respectively. After 10 days of cholesterol feeding, the bile acid pool size increased nearly 2-fold. SHP mRNA levels increased 4.1-fold while CYP8B declined 64%. ABCA1 mRNA rose 8-fold and CETP mRNA remained elevated. Activity and mRNA of CYP7A1 decreased 60% and 90%, respectively. Feeding cholesterol for 1 day did not enlarge the ligand pool size or change FXR activation, while LXRalpha was activated highly secondary to increased hepatic oxysterols. As a result, CYP7A1 was up-regulated. After 10 days of cholesterol feeding, the bile acid (FXR ligand) pool size increased, which activated FXR and inhibited CYP7A1 despite continued activation of LXRalpha. Thus, in rabbits, when FXR and LXRalpha are activated simultaneously, the inhibitory effect of FXR overrides the stimulatory effect of LXRalpha to suppress CYP7A1 mRNA expression.
authors.affiliation: Medical Service, Veteran's Administration Medical Center, East Orange, NJ 07018, USA. xugu@umdnj.edu
authors.forename: Guorong
authors.initials: G
authors.lastname: Xu
authors.forename: Hai
authors.initials: H
authors.lastname: Li
authors.forename: Lu-Xing
authors.initials: LX
authors.lastname: Pan
authors.forename: Quan
authors.initials: Q
authors.lastname: Shang
authors.forename: Akira
authors.initials: A
authors.lastname: Honda
authors.forename: M
authors.initials: M
authors.lastname: Ananthanarayanan
authors.forename: Sandra K
authors.initials: SK
authors.lastname: Erickson
authors.forename: Benjamin L
authors.initials: BL
authors.lastname: Shneider
authors.forename: Sarah
authors.initials: S
authors.lastname: Shefer
authors.forename: Jaya
authors.initials: J
authors.lastname: Bollineni
authors.forename: Barry M
authors.initials: BM
authors.lastname: Forman
authors.forename: Yasushi
authors.initials: Y
authors.lastname: Matsuzaki
authors.forename: Frederick J
authors.initials: FJ
authors.lastname: Suchy
authors.forename: G Stephen
authors.initials: GS
authors.lastname: Tint
authors.forename: Gerald
authors.initials: G
authors.lastname: Salen
mesh_terms: D018528:ATP-Binding Cassette Transporters / Q000378:metabolism; D000818:Animals; D001647:Bile Acids and Salts / Q000378:metabolism; D002352:Carrier Proteins / Q000378:metabolism; D002784:Cholesterol / Q000008:administration & dosage* / Q000378:metabolism; D002790:Cholesterol 7-alpha-Hydroxylase / Q000378:metabolism*; D053480:Cholesterol Ester Transfer Proteins; D004268:DNA-Binding Proteins / Q000378:metabolism*; D015536:Down-Regulation; D006023:Glycoproteins / Q000378:metabolism; D008024:Ligands; D008099:Liver / Q000378:metabolism; D000071518:Liver X Receptors; D057093:Orphan Nuclear Receptors; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D011817:Rabbits; D018160:Receptors, Cytoplasmic and Nuclear / Q000378:metabolism*; D011987:Receptors, Steroid / Q000378:metabolism; D013253:Steroid 12-alpha-Hydroxylase / Q000378:metabolism; D013997:Time Factors; D014157:Transcription Factors / Q000378:metabolism*; D000099150:Receptor, Farnesoid X-Activated
chemical_list: D018528:ATP-Binding Cassette Transporters; D001647:Bile Acids and Salts; D002352:Carrier Proteins; D002784:Cholesterol; D002790:Cholesterol 7-alpha-Hydroxylase; D053480:Cholesterol Ester Transfer Proteins; D004268:DNA-Binding Proteins; D006023:Glycoproteins; D008024:Ligands; D000071518:Liver X Receptors; D057093:Orphan Nuclear Receptors; D012333:RNA, Messenger; D018160:Receptors, Cytoplasmic and Nuclear; D011987:Receptors, Steroid; D013253:Steroid 12-alpha-Hydroxylase; D014157:Transcription Factors; D000099150:Receptor, Farnesoid X-Activated