Pregnane X Receptor-4 beta-Hydroxycholesterol Axis in the Regulation of Overweight- and Obesity-Induced Hypertension

BACKGROUND: Mechanisms mediating hypertensive effects of overweight and obesity have not been fully elucidated. We showed previously that activation of pregnane X receptor (PXR) by rifampicin elevates 24-hour blood pressure (BP) and plasma 4 beta-hydroxycholesterol (4 beta HC), agonist for liver X receptor (LXR). METHODS AND RESULTS: In combined "PXR activation data set" (n=62) of 4 clinical trials, 1 week rifampicin dosing increased office systolic BP (SBP) by 3.1 mm Hg, DBP 1.8 mm Hg, and mean arterial pressure 2.2 mm Hg in comparison with placebo (P<0.01). Plasma 4 beta HC had negative correlation with SBP both in rifampicin (r=-0.46, P=0.0002) and placebo (r=-0.45, P=0.0003) arms, although 4 beta HC was elevated >3-fold by rifampicin. In "non-intervention data set" (n=102) of patients with obesity and healthy volunteers (body mass index, 19.2-55.2 kg/m(2)), 4 beta HC had negative correlations (P<0.00001) with office SBP (r=-0.51), diastolic BP (r=-0.50), and mean arterial pressure (r=-0.54). Lean women had higher 4 beta HC than men, with increasing weight repressing 4 beta HC (r=- 0.62, P<0.00001) in both sexes. In multiple linear regression analysis, the only statistically significant predictor for SBP was 4 beta HC. Six-day PXR agonist dosing elevated SBP in rats (n=7-8/group). PXR activation elevated 4 beta HC and after PXR agonist was withdrawn and elevated 4 beta HC was left to act alone, SBP was reduced on days 7 to 14 in comparison with control rats. CONCLUSIONS: PXR activation elevates SBP. Elevated circulating 4 beta HC lowers SBP in rats, and higher 4 beta HC is an independent predictor of lower SBP in humans. PXR-4 beta HC-LXR is novel BP-regulating pathway deregulated in overweight and obesity by repressed 4 beta HC, with implications for sex-specific BP regulation.