Journal
JOURNAL OF THE AMERICAN HEART ASSOCIATION
Volume 11, Issue 6, Pages -Publisher
WILEY
DOI: 10.1161/JAHA.121.023492
Keywords
4 beta-hydroxycholesterol; blood pressure; liver X receptor; obesity; pregnane X receptor
Categories
Funding
- Diabetes Research Foundation
- Finnish Foundation for Cardiovascular Research
- Northern Finland Health Care Support Foundation
- Finnish Government Grants for Health Research
- Finnish Medical Foundation
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This study found that activation of PXR can increase blood pressure, while elevated 4-beta hydroxycholesterol in circulation can lower blood pressure. It was also found that 4-beta hydroxycholesterol in the blood is negatively correlated with blood pressure in obese patients and healthy volunteers. This study reveals a new hypertension regulating pathway associated with overweight and obesity.
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 PXR activation elevated 4 beta HC and after PXR agonist was withdrawn and elevated 4 beta HC was left to act alone, SBP was reduced on days 7 to 14 in comparison with control rats.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.
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