Hypertension in Overweight and Obesity: Sex-Specific Role of 4β-Hydroxycholesterol

We have previously proposed novel pathway in overweight/obesity-induced hypertension involving plasma 4β-hydroxycholesterol (4βHC), an agonist for LXR (liver X receptor), as a hypotensive factor. The aim was to determine sex-specific roles of 4βHC in obesity-induced hypertension in a cohort without blood pressure (BP) medications.

A study population (n=645) with wide body mass index range (19-47 kg/m²) was analyzed for plasma 4βHC. Factors determining BP were analyzed in multiple linear regression analyses. Also, sex-specific effects of pharmacologically elevated 4βHC, achieved through rifampicin administration, were evaluated.

Plasma 4βHC correlated negatively with systolic BP and body mass index in both sexes. In men (n=282), the correlation between 4βHC and systolic BP was r=-0.19 (P=0.002) and in women (n=363) r=-0.20 (P<0.001). Correlation between plasma 4βHC and BMI in men was r=-0.44 (P<0.001), and women r=-0.37 (P<0.001). In a multiple linear regression with both sexes included, plasma 4βHC along with age, body mass index, and low-density lipoprotein cholesterol predicted systolic BP. In men, only age and body mass index were predictors of systolic BP, whereas in women, only age and 4βHC were significant factors. The same sex-specific pattern regarding 4βHC was detected for diastolic BP and mean arterial pressure. However, in men, the pharmacologic 4βHC elevation strengthened the inverse correlations between BP indices and 4βHC, whereas in women these associations were weakened.

Plasma 4βHC was associated inversely with BP, especially in women, whereas pharmacologically elevated 4βHC seemed to affect men more pronouncedly. Plasma 4βHC may have a sex-specific role in overweight- and obesity-induced hypertension.

URL: https://www.clinicaltrials.gov; Unique Identifiers: NCT00985270, NCT01293422, NCT01690104, NCT02329405, NCT01330251, NCT01959763, and NCT04558801.