Research Unit of Internal Medicine University of Oulu Finland.
Biocenter Oulu University of Oulu Finland.
J Am Heart Assoc. 2022 Mar 15;11(6):e023492. doi: 10.1161/JAHA.121.023492. Epub 2022 Mar 1.
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 (<0.01). Plasma 4βHC had negative correlation with SBP both in rifampicin (=-0.46, =0.0002) and placebo (=-0.45, =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), 4βHC had negative correlations (<0.00001) with office SBP (=-0.51), diastolic BP (=-0.50), and mean arterial pressure (=-0.54). Lean women had higher 4βHC than men, with increasing weight repressing 4βHC (=-0.62, <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 PXR activation elevated 4βHC and after PXR agonist was withdrawn and elevated 4βHC was left to act alone, SBP was reduced on days 7 to 14 in comparison with control rats.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.
超重和肥胖导致高血压的机制尚未完全阐明。我们之前的研究表明，利福平激活孕烷 X 受体（PXR）可升高 24 小时血压（BP）和血浆 4β-羟胆固醇（4βHC），后者是肝 X 受体（LXR）的激动剂。
在 4 项临床试验的“PXR 激活数据组”（n=62）中，与安慰剂相比，1 周利福平治疗可使诊室收缩压（SBP）升高 3.1mmHg，舒张压（DBP）升高 1.8mmHg，平均动脉压升高 2.2mmHg（<0.01）。尽管利福平使 4βHC 升高了>3 倍，但血浆 4βHC 与利福平（=-0.46，=0.0002）和安慰剂（=-0.45，=0.0003）组的 SBP 呈负相关。在肥胖患者和健康志愿者（体重指数 19.2-55.2kg/m）的“非干预数据组”（n=102）中，4βHC 与诊室 SBP（=-0.51）、舒张压（=-0.50）和平均动脉压（=-0.54）呈负相关（<0.00001）。瘦女性的 4βHC 高于男性，体重增加抑制 4βHC（=-0.62，<0.00001），两性均如此。在多元线性回归分析中，SBP 的唯一统计学显著预测因子是 4βHC。6 天 PXR 激动剂治疗可使大鼠 SBP 升高（n=7-8/组）。PXR 激活可升高 4βHC，PXR 激动剂停药后，升高的 4βHC 单独作用，与对照组大鼠相比，SBP 在第 7 至 14 天下降。
PXR 激活可升高 SBP。升高的循环 4βHC 可降低大鼠 SBP，而较高的 4βHC 是人类 SBP 降低的独立预测因子。PXR-4βHC-LXR 是超重和肥胖患者中调节血压的新途径，该途径通过抑制 4βHC 而失调，对性别特异性血压调节具有重要意义。
https://www.clinicaltrials.gov；唯一标识符：NCT00985270、NCT01293422、NCT01690104、NCT02329405 和 NCT01330251。
