Pregnane X Receptor‒4β-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 4β-hydroxycholesterol (4βHC), 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 4βHC had negative correlation with SBP both in rifampicin ( r =-0.46, P =0.0002) and placebo ( r =-0.45, P =0.0003) arms, although 4βHC 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 ), 4βHC 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 4βHC than men, with increasing weight repressing 4βHC ( r =-0.62, P <0.00001) in both sexes. In multiple linear regression analysis, the only statistically significant predictor for SBP was 4βHC. Six-day PXR agonist dosing elevated SBP in rats (n=7-8/group). PXR activation elevated 4βHC and after PXR agonist was withdrawn and elevated 4βHC was left to act alone, SBP was reduced on days 7 to 14 in comparison with control rats.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 4βHC lowers SBP in rats, and higher 4βHC is an independent predictor of lower SBP in humans. PXR-4βHC-LXR is novel BP-regulating pathway deregulated in overweight and obesity by repressed 4βHC, with implications for sex-specific BP regulation. Registration URL: https://www.clinicaltrials.gov; Unique identifiers: NCT00985270, NCT01293422, NCT01690104, NCT02329405, and NCT01330251.