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

Abstract

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/m2), 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 PXR activation elevated 4βHC and after PXR agonist was withdrawn and elevated 4βHC was left to act alone, SBP was reduced on days 7 to 14 in comparison with control rats.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.

Keywords: 4β‐hydroxycholesterol; blood pressure; liver X receptor; obesity; pregnane X receptor.

Figures

Figure 1. Effect of the treatment with 600 mg rifampicin or placebo once daily for 1 week on blood pressure and blood pressure‐regulating factors in healthy volunteers of the “pregnane X receptor activation data set” (n=62, except for 4β‐hydroxycholesterol analysis n=61).

Center line, mean; box limits, upper and lower quartiles; whiskers, minimum and maximum values. 4βHC indicates 4β‐hydroxycholesterol; and BP, blood pressure.

Figure 2. Correlation between plasma 4β‐hydroxycholesterol and systolic blood pressure in the rifampicin and placebo arms in healthy volunteers of the “pregnane X receptor activation data set” (n=61).

Pearson correlation coefficients were calculated to analyze the correlation of 4β‐hydroxycholesterol with systolic blood pressure. 4βHC indicates 4β‐hydroxycholesterol; and BP, blood pressure.

Figure 3. The factors affecting plasma 4β‐hydroxycholesterol concentration.

A, Predictors for 4β‐hydroxycholesterol in multiple linear regression analysis in the “non‐intervention data set” including healthy volunteers and patients with obesity (n=102). B, Individual 4β‐hydroxycholesterol values in 4 body mass index ranges according to sex. Values in the bar graphs are represented as means±SD. *P<0.001, unpaired 2‐tailed Student t‐test. 4βHC indicates 4β‐hydroxycholesterol; and BMI, body mass index. Bold indicates statistically significant factors in the final model.

Figure 4. Correlation of plasma 4β‐hydroxycholesterol with (A) systolic blood pressure and (B) body mass index in the “non‐intervention data set” including healthy volunteers and patients with obesity (n=102).

Pearson correlation coefficients were calculated to analyze the correlation of 4βHC with systolic blood pressure and body mass index. Values in the bar graphs are represented as means±SD. 4βHC indicates 4β‐hydroxycholesterol; BP, blood pressure; and BMI, body mass index.

Figure 5. Effect of intraperitoneal pregnenolone 16α‐carbonitrile vs vehicle control for 6 days on incremental systolic blood pressure, mean arterial pressure, diastolic blood pressure, and heart rate in rats followed for total of 14 days.

Pregnenolone 16α‐carbonitrile dosing increased systolic blood pressure during the first 3 days (P=0.029, see Table 4). After pregnenolone 16α‐carbonitrile was withdrawn and elevated 4β‐hydroxycholesterol was left to act alone (days 7–14), systolic blood pressure and heart rate were lowered (P=0.040 and 0.014, respectively, see Table 4). Mann‐Whitney U test was the statistical test used. Values are represented as means±SD. 4βHC indicates 4β‐hydroxycholesterol; BP, blood pressure; i.p., intraperitoneal; MAP, mean arterial pressure; and PCN, pregnenolone 16α‐carbonitrile.