PXR and the regulation of apoA1 and HDL-cholesterol in rodents

• Published in: Pharmacological research 2004-09, Vol.50 (3), p.237-246
• Main Authors: Bachmann, Kenneth, Patel, Hiral, Batayneh, Zaid, Slama, James, White, Donald, Posey, Julie, Ekins, Sean, Gold, David, Sambucetti, Lidia
• Format: Article
• Language: English
• Subjects: Animals; apoA1; Apolipoprotein A-I - blood; Cholesterol, HDL - blood; Clotrimazole - chemistry; Clotrimazole - pharmacology; CYP enzymes; HDL-cholesterol; Humans; Imidazoles - chemistry; Imidazoles - pharmacology; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Orphan nuclear receptors; PXR; Rats; Rats, Sprague-Dawley; Receptors, Cytoplasmic and Nuclear - agonists; Receptors, Cytoplasmic and Nuclear - deficiency; Receptors, Cytoplasmic and Nuclear - physiology; Receptors, Steroid - agonists; Receptors, Steroid - deficiency; Receptors, Steroid - physiology
• ISSN: 1043-6618; 1096-1186
• DOI: 10.1016/j.phrs.2004.03.005

Orphan nuclear receptors (ONRs) have been implicated in the regulation of lipids. Several clinical studies conducted either prospectively or epidemiologically have pointed to a link between the regulation of hepatic CYP enzymes and HDL-cholesterol (HDL-C) and/or apolipoprotein A1 (apoA1). The treatment of rats with a series of imidazole inducers of CYP3A yielded correlations between in vitro CYP3A activity measured as erythromycin demethylase activity and plasma HDL-C and hepatic apoA1 mRNA. Similarly, a correlation was established between in vivo CYP3A activity, measured as ethosuximide clearance, and plasma HDL-C and hepatic apoA1 mRNA. The treatment of wild-type (WT) mice with PXR agonists elicited increases in serum HDL-C and serum apoA1 levels. On the other hand, the treatment of PXR-knockout mice (PXR-KOs) with the same PXR agonists failed to elicit increases in either serum HDL-C or serum apoA1 levels. Superposition of the structures of three imidazoles known to be active CYP3A inducers in rats with the human PXR pharmacophore demonstrated a partial fit and predicted EC 50 values typical of weak-moderate hPXR inducers in humans. These imidazoles have been shown to increase apoA1 and HDL-C in rats and mice. Taken together, these data suggest that PXR plays an important role in the regulation of apoA1 and HDL-C in rodents.