Dietary cholesterol stimulates CYP7A1 in rats because farnesoid X receptor is not activated.
Cholesterol feeding upregulates CYP7A1 in rats but downregulates CYP7A1 in rabbits. To clarify the mechanism responsible for the upregulation of CYP7A1 in cholesterol-fed rats, the effects of dietary cholesterol (Ch) and cholic acid (CA) on the activation of the nuclear receptors, liver X-receptor (LXR-alpha) and farsenoid X-receptor (FXR), which positively and negatively regulate CYP7A1, were investigated in rats. Studies were carried out in four groups (n = 12/group) of male Sprague-Dawley rats fed regular chow (control), 2% Ch, 2% Ch + 1% CA, and 1% CA alone for 1 wk. Changes in mRNA expression of short heterodimer partner (SHP) and bile salt export pump (BSEP), target genes for FXR, were determined to indicate FXR activation, whereas the expression of ABCA1 and lipoprotein lipase (LPL), target genes for LXR-alpha, reflected activation. CYP7A1 mRNA and activity increased twofold and 70%, respectively, in rats fed Ch alone when the bile acid pool size was stable but decreased 43 and 49%, respectively, after CA was added to the Ch diet, which expanded the bile acid pool 3.4-fold. SHP and BSEP mRNA levels did not change after feeding Ch but increased 88 and 37% in rats fed Ch + CA. This indicated that FXR was activated by the expanded bile acid pool. When Ch or Ch + CA were fed, hepatic concentrations of oxysterols, ligands for LXR-alpha increased to activate LXR-alpha, as evidenced by increased mRNA levels of ABCA1 and LPL. Feeding CA alone enlarged the bile acid pool threefold and increased the expression of both SHP and BSEP. These results suggest that LXR-alpha was activated in rats fed both Ch or Ch + CA, whereas CYP7A1 mRNA and activity were induced only in Ch-fed rats where the bile acid pool was not enlarged such that FXR was not activated. In rats fed Ch + CA, the bile acid pool expanded, which activated FXR to offset the stimulatory effects of LXR-alpha on CYP7A1.
Xu
Guorong
G
Gastrointestinal Lab (15A Veterans Affairs Medical Center, 385 Tremont Ave., East Orange, NJ 07018-1095, USA. xugu@umdnj.edu
Pan
Lu-Xing
LX
Li
Hai
H
Shang
Quan
Q
Honda
Akira
A
Shefer
Sarah
S
Bollineni
Jaya
J
Matsuzaki
Yasushi
Y
Tint
G Stephen
GS
Salen
Gerald
G
D000074020:ATP Binding Cassette Transporter, Subfamily B, Member 11; D018528:ATP-Binding Cassette Transporters / Q000235:genetics; D000818:Animals; D002790:Cholesterol 7-alpha-Hydroxylase / Q000235:genetics / Q000378:metabolism*; D002791:Cholesterol, Dietary / Q000494:pharmacology*; D019826:Cholic Acid / Q000008:administration & dosage; D004268:DNA-Binding Proteins / Q000502:physiology*; D004032:Diet; D004357:Drug Synergism; D000071518:Liver X Receptors; D008297:Male; D057093:Orphan Nuclear Receptors; D020033:Protein Isoforms / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D018160:Receptors, Cytoplasmic and Nuclear / Q000235:genetics; D014157:Transcription Factors / Q000502:physiology*; D015854:Up-Regulation; D000099150:Receptor, Farnesoid X-Activated
D000074020:ATP Binding Cassette Transporter, Subfamily B, Member 11; D018528:ATP-Binding Cassette Transporters; D002790:Cholesterol 7-alpha-Hydroxylase; D002791:Cholesterol, Dietary; D019826:Cholic Acid; D004268:DNA-Binding Proteins; D000071518:Liver X Receptors; D057093:Orphan Nuclear Receptors; D020033:Protein Isoforms; D012333:RNA, Messenger; D018160:Receptors, Cytoplasmic and Nuclear; D014157:Transcription Factors; D000099150:Receptor, Farnesoid X-Activated; C490548:Abcb11 protein, rat; C000605215:Nr1h3 protein, rat; C099713:nuclear receptor subfamily 0, group B, member 2