OR11-06 Biological Activity Of Lumisterol Hydroxymetabolites And Their Mechanism Of Action

Abstract Disclosure: A. Slominski: None. T. Kim: None. E. Podgorska: None. Z. Janjetovic: None. J. Stefan: None. S. Ravichandran: None. R.M. Slominski: None. Y. Song: None. Y. Song: None. J. Szpotan: None. A. Mobley: None. C. Raman: None. E. Tang: None. A.M. Jetten: None. M.F. Holick: None. R. Tuckey: None. While the role of vitamin D3 in body homeostasis is well established, the functions of its photoderivative, lumisterol (L3), are gradually being appreciated. Previously, we reported that L3 can be metabolized by CYP11A1 and CYP27A1 to mono- and dihydroxy-L3. Furthermore, we have shown that 7DHC reductase (DHCR7) does not act on L3 and its metabolites [(OH)nL3]. In the current study, we show the presence of CYP27A1-derived 25(OH)L3, (25R)27(OH)L3 and (25S)27(OH)L3 in human epidermis and serum, and the capability by human keratinocytes to generate them from L3 substrate. Furthermore, these metabolites inhibited keratinocyte proliferation and stimulated cell differentiation. They, together with CYP11A1-derived (OH)nL3 acted as ligands on the human aryl hydrocarbon (AhR), liver X (LXR α and β), and peroxisome proliferator-activated (PPARγ) receptors as demonstrated by functional assays, molecular modeling, and activation of the CYP1A1 and CYP1B1, which are downstream of the AhR. These findings indicate that these hydroxyderivatives can regulate physiological functions by acting on AhR, LXRs and PPARγ receptors and activate respective downstream signaling pathways. Thus, L3 produced in the skin by UVB, can act as a pro-hormone that is metabolized into biologically active metabolites by CYP11A1 and CYP27A1 that can not only regulate skin functions but also other biological functions after their entry into the systemic circulation. These findings open, previously unanticipated, exciting new areas of research on the physiological role of (OH)nL3, and L3 through action on AhR, LXRs and PPARγ receptors. Presentation: Friday, June 16, 2023