PXR and the regulation of apoA1 and HDL-cholesterol in rodents.
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.
Bachmann
Kenneth
K
Department of Pharmacology, University of Toledo, 2801 W. Bancroft St., Toledo, OH 43606, USA. kbachma@utnet.utoledo.edu
Patel
Hiral
H
Batayneh
Zaid
Z
Slama
James
J
White
Donald
D
Posey
Julie
J
Ekins
Sean
S
Gold
David
D
Sambucetti
Lidia
L
D000818:Animals; D016632:Apolipoprotein A-I / Q000097:blood*; D008076:Cholesterol, HDL / Q000097:blood*; D003022:Clotrimazole / Q000737:chemistry / Q000494:pharmacology; D006801:Humans; D007093:Imidazoles / Q000737:chemistry / Q000494:pharmacology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D000077297:Pregnane X Receptor; D051381:Rats; D017207:Rats, Sprague-Dawley; D018160:Receptors, Cytoplasmic and Nuclear / Q000819:agonists* / Q000172:deficiency / Q000502:physiology*; D011987:Receptors, Steroid / Q000819:agonists* / Q000172:deficiency / Q000502:physiology*
D016632:Apolipoprotein A-I; D008076:Cholesterol, HDL; D007093:Imidazoles; D000077297:Pregnane X Receptor; D018160:Receptors, Cytoplasmic and Nuclear; D011987:Receptors, Steroid; D003022:Clotrimazole