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27-Hydroxycholesterol: the first identified endogenous SERM

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The cholesterol metabolite 27-hydroxycholesterol (27OHC) classically delivers sterols from peripheral tissues to the liver and is a substrate for bile acid synthesis. Recent studies have revealed that 27OHC also binds to and modifies the function of estrogen receptors ERα and ERβ. Experiments in mice lacking the enzyme which synthesizes 27OHC, CYP27A1, or the enzyme which catabolizes 27OHC, CYP7B1, have demonstrated that 27OHC adversely affects estrogen-related cardiovascular protection and bone mineralization. Work in breast cancer cells further indicates that 27OHC alters ER target gene expression to promote cell growth. Therefore, 27OHC is the first identified endogenous selective estrogen receptor modulator (SERM) and could have an important impact upon the cardiovascular system, bone biology, and cancer.

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Selective estrogen receptor modulators

Selective estrogen receptor modulators, or SERMs, have both agonist and antagonist activities involving high-affinity interactions with estrogen receptors (ER) and cause unique changes in ER conformation that are distinct from those induced by binding of naturally-occurring forms of estrogen to the receptor. Following receptor binding, both ERα or ERβ selectively recruit and interact with coactivators and corepressors, and SERMs thereby cause several different responses that are cell-type

27OHC as an oxysterol

Oxysterols are metabolites of cholesterol containing one or more hydroxyl groups, principally on the side chain, and they serve multiple roles in lipid metabolism. They are important in reverse cholesterol transport that delivers sterols from peripheral tissues to the liver, primarily as components of low-density lipoprotein cholesterol (LDL) or high-density lipoprotein cholesterol (HDL) particles, and predominantly in esterified form due to the actions of lecithin-cholesterol acyltransferase

27OHC as a SERM

Until recently the only recognized SERMs were synthetic molecules. The first evidence that 27OHC is a SERM came from Gal4–ER cotransfection assays testing ERα and ERβ function in HEK293 cells. Of the series of abundant endogenous oxysterols tested, 22R-hydroxycholesterol, 24S-hydroxycholesterol, 25OHC and 27OHC inhibited 17β-estradiol (E2) activation of ERα and ERβ with IC50 values ranging from 1–5 μM for both ERs. 27OHC was the most potent oxysterol (IC50 = 1 μM), with 90% efficacy on ERβ and

27OHC levels in health and disease

As noted, the majority of circulating 27OHC is transported in association with LDL and HDL cholesterol. There are no significant diurnal changes and, in healthy volunteers, plasma and the non-HDL subfraction concentrations of 27OHC are strongly correlated with the concentrations of cholesterol, non-HDL cholesterol and triglycerides. Circulating levels of 27OHC increase with age, particularly after the age of 30, and they are believed to be derived primarily from extrahepatic sources 10, 19, 20.

Impact of 27OHC on the cardiovascular system

ERs regulate many physiologic processes in addition to reproduction [24]. The cardiovascular system is a potentially important physiologic as well as pharmacologic target of ER action, and the effects of E2 on endothelial and vascular smooth muscle (VSM) cells are believed to be beneficial [25]. In mice, ERα is required for the maintenance and repair of vascular endothelium through actions that include the upregulation of endothelial NO synthase (eNOS) expression and the unique stimulation of

Impact of 27OHC on breast cancer

Breast cancer is the most common malignancy in women other than skin cancer; approximately one million new cases are diagnosed worldwide each year [42] and postmenopausal women are particularly at increased risk of ER(+) breast cancer [43]. This risk occurs at a time when circulating estrogen levels are declining, and endocrine-based therapies against ER(+) breast cancer employing synthetic SERMs or aromatase inhibition are often ineffective or resistance develops [43], suggesting that other

Impact of 27OHC on bone mineralization

In addition to its actions in the cardiovascular system and on tumor growth, estrogen plays an important role in the regulation of bone mineralization, and estrogen deficiency caused by menopause or ovariectomy results in pathological bone loss that can be reversed by estrogen replacement 24, 45. Recognition of the importance of estrogen in bone homeostasis, and reports that hypercholesterolemia is an independent risk factor for decreased bone mass in postmenopausal women 46, 47, pointed to

Future directions

Nearly 50 years after the functions of the first synthetic SERM tamoxifen were delineated, the oxysterol 27OHC was identified as the first endogenous SERM. Studies in mice with alterations in 27OHC abundance have indicated that 27OHC has adverse effects on the cardiovascular protection afforded by estrogen and also on bone mineralization. Work in cell culture has revealed that 27OHC is an endogenous ligand capable of activating breast cancer cell growth. Numerous gaps in our knowledge remain.

Acknowledgments

The authors thank their colleagues and collaborators who have made important contributions to our understanding of the biology of 27OHC, both in cholesterol and bile acid homeostasis and as a SERM. These include David Mangelsdorf and David Russell at University of Texas Southwestern, and Carolyn DuSell and Donald McDonnell at Duke University Medical Center. This work was supported by National Institutes of Health grants DK079328 (MU) and HL087564 (PS).

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