27-Hydroxycholesterol is an endogenous SERM that inhibits the cardiovascular effects of estrogen

Abstract

The cardioprotective effects of estrogen are mediated by receptors expressed in vascular cells. Here we show that 27-hydroxycholesterol (27HC), an abundant cholesterol metabolite that is elevated with hypercholesterolemia and found in atherosclerotic lesions, is a competitive antagonist of estrogen receptor action in the vasculature. 27HC inhibited both the transcription-mediated and the non-transcription-mediated estrogen-dependent production of nitric oxide by vascular cells, resulting in reduced estrogen-induced vasorelaxation of rat aorta. Furthermore, increasing 27HC levels in mice by diet-induced hypercholesterolemia, pharmacologic administration or genetic manipulation (by knocking out the gene encoding the catabolic enzyme CYP7B1) decreased estrogen-dependent expression of vascular nitric oxide synthase and repressed carotid artery reendothelialization. As well as antiestrogenic effects, there were proestrogenic actions of 27HC that were cell-type specific, indicating that 27HC functions as an endogenous selective estrogen receptor modulator (SERM). Taken together, these studies point to 27HC as a contributing factor in the loss of estrogen protection from vascular disease.

Usefulness of Baseline Lipids and C-Reactive Protein in Women Receiving Menopausal Hormone Therapy as Predictors of Treatment-Related Coronary Events

“…Our study specifically excluded women with prior CHD, yet we still observed an interaction between hormone therapy and baseline cholesterol levels for CHD risk even after adjusting for age. Recently, the cholesterol metabolite, 27-hydroxycholesterol, has been shown to compete with estrogen for binding to vascular estrogen receptors, blocking the beneficial effects of estrogen (nitric oxide production and endothelial cell migration) on murine vascular cells 11 . This study by Umetani et al suggests an attractive and testable hypothesis: that postmenopausal women with a poor lipid profile have elevated levels of 27-hydroxycholesterol, which disables a potential vascular benefit of estrogen.…”

Insights from the structure of estrogen receptor into the evolution of estrogens: Implications for endocrine disruption

“…Recently, Umetani et al [40] reported that several hydroxylated cholesterols including 27-hydroxycholesterol [27-OH-C], 22R-OH-C, 24S-OH-C and 25-OH-C bound human ER and human ER . 27-OH-C was the most potent, and in some mammalian cells 27-OH-C functions as a partial agonist for human ER and ER [40][41][42][43].…”

“…Recently, Umetani et al [40] reported that several hydroxylated cholesterols including 27-hydroxycholesterol [27-OH-C], 22R-OH-C, 24S-OH-C and 25-OH-C bound human ER and human ER . 27-OH-C was the most potent, and in some mammalian cells 27-OH-C functions as a partial agonist for human ER and ER [40][41][42][43]. The Kd of 27-OH-C for ER and ER is about 1.3 M and 0.4 M, respectively [40][41][42], which is over 10 3 times higher than the Kd of E2 for human ER and ER [30,40].…”

“…27-OH-C was the most potent, and in some mammalian cells 27-OH-C functions as a partial agonist for human ER and ER [40][41][42][43]. The Kd of 27-OH-C for ER and ER is about 1.3 M and 0.4 M, respectively [40][41][42], which is over 10 3 times higher than the Kd of E2 for human ER and ER [30,40]. Nevertheless, a Kd of 1 M is physiologically relevant because the circulating concentration of 27-OH-C is from 0.15 to 0.73 M, [40][41][42].…”

“…His-524 on ER does not contact the 27-hydroxyl, which may explain the substantially the lower affinity of 27-OH-C for ER and ER [40][41][42].…”