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 PXR activation elevated 4βHC and after PXR agonist was withdrawn and elevated 4βHC was left to act alone, SBP was reduced on days 7 to 14 in comparison with control rats.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.