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.
Highlights
We investigated how cholesterol feeding regulates cholesterol 7␣-hydroxylase (CYP7A1) via the nuclear receptors farnesoid X receptor (FXR) and liver X receptor ␣ (LXR␣) in New Zealand white rabbits
ATP binding cassette transporter A1 (ABCA1) [24] and cholesteryl ester transfer protein (CETP) [25] are target genes positively regulated by LXR␣
As there is no method available to measure directly the activation of FXR and LXR␣ in whole-animal models, we measured the mRNA expression of regulated target genes for FXR (SHP, bile salt export pump (BSEP), and CYP8B) and LXR␣ (ABCA1 and CETP) to indicate the activation state of the nuclear receptors
Summary
We investigated how cholesterol feeding regulates cholesterol 7␣-hydroxylase (CYP7A1) via the nuclear receptors farnesoid X receptor (FXR) and liver X receptor ␣ (LXR␣) 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 12␣-hydroxylase (CYP8B) were unchanged, indicating that FXR activation remained constant. After 10 days of cholesterol feeding, the bile acid (FXR ligand) pool size increased, which activated FXR and inhibited CYP7A1 despite continued activation of LXR␣. As there is no method available to measure directly the activation of FXR and LXR␣ in whole-animal models, we measured the mRNA expression of regulated target genes for FXR (SHP, BSEP, and CYP8B) and LXR␣ (ABCA1 and CETP) to indicate the activation state of the nuclear receptors. After 10 days of cholesterol feeding, both FXR and LXR␣ were simultaneously activated, but CYP7A1 was inhibited markedly These observations suggest that in cholesterol-fed NZW rabbits, the inhibitory effect of activated FXR on CYP7A1 transcription overrides the stimulatory effect of activated LXR␣
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
