Re-adopting classical nuclear receptors by cholesterol metabolites

• 27HC was the first identified endogenous SERM.
• 27HC inhibits estrogen’s cardioprotective effects and stimulates inflammation in vasculature.
• 27HC is estrogenic in breast cancer, and its tissue levels increase with disease stage in patients.
• 27HC negatively regulates bone mineralization through effects on ER and LXR.
• LXR stimulates the nonnuclear action of ERα and exerts vascular protection.

Since the first cloning of the human estrogen receptor (ER) α in 1986 and the subsequent cloning of human ERβ, there has been extensive investigation of the role of estrogen/ER. Estrogens/ER play important roles not only in sexual development and reproduction but also in a variety of other functions in multiple tissues. Selective Estrogen Receptor Modulators (SERMs) are ER lignds that act as agonists or antagonists depending on the target genes and tissues, and until recently, only synthetic SERMs have been recognized. However, the discovery of the first endogenous SERM, 27-hydroxycholesterol (27HC), opened a new dimension of ER action in health and disease. In addition to the identification of 27HC as a SERM, oxysterols have been recently demonstrated as indirect modulators of ER through interaction with the nuclear receptor Liver X Receptor (LXR) β. In this review, the recent progress on these novel roles of oxysterols in ER modulation is summarized.