Attenuation of UVR-induced vitamin D 3 synthesis in a mouse model deleted for keratinocyte lathosterol 5-desaturase

• Published in: The Journal of steroid biochemistry and molecular biology 2017-07, Vol.171, p.187
• Main Authors: Makarova, Anastasia M, Pasta, Saloni, Watson, Gordon, Shackleton, Cedric, Epstein, Jr, Ervin H
• Format: Article
• Language: English
• Subjects: Animals; Cholecalciferol - biosynthesis; Cholecalciferol - blood; Cholesterol - metabolism; Crosses, Genetic; Dehydrocholesterols - metabolism; Disease Models, Animal; Female; Hair - metabolism; Heterozygote; Kaplan-Meier Estimate; Keratinocytes - metabolism; Keratinocytes - pathology; Keratinocytes - radiation effects; Male; Metabolism, Inborn Errors - blood; Metabolism, Inborn Errors - genetics; Metabolism, Inborn Errors - metabolism; Metabolism, Inborn Errors - pathology; Mice, Inbred C57BL; Mice, Knockout; Mice, Transgenic; Oxidoreductases Acting on CH-CH Group Donors - deficiency; Oxidoreductases Acting on CH-CH Group Donors - genetics; Oxidoreductases Acting on CH-CH Group Donors - metabolism; Pregnancy; Random Allocation; Skin - metabolism; Skin - pathology; Skin - radiation effects; Ultraviolet Rays
• ISSN: 1879-1220
• DOI: 10.1016/j.jsbmb.2017.03.017

The lower risk of some internal cancers at lower latitudes has been linked to greater sun exposure and consequent higher levels of ultraviolet radiation (UVR)-produced vitamin D (D ). To separate the experimental effects of sunlight and of all forms of D , a mouse in which UVR does not produce D would be useful. To this end we have generated mice carrying a modified allele of sterol C5-desaturase (Sc5d), the gene encoding the enzyme that converts lathosterol to 7-dehydrocholesterol (7-DHC), such that Sc5d expression can be inactivated using the Cre/lox site-specific recombination system. By crossing to mice with tissue-specific expression of Cre or CreER (Cre/estrogen receptor), we generated two lines of transgenic mice. One line has constitutive keratinocyte-specific inactivation of Sc5d (Sc5d ). The other line (Sc5d ) has tamoxifen-inducible keratinocyte-specific inactivation of Sc5d. Mice deleted for keratinocyte Sc5d lose the ability to increase circulating D following UVR exposure of the skin. Thus, unlike in control mice, acute UVR exposure did not affect circulating D level in inducible Sc5d mice. Keratinocyte-specific inactivation of Sc5d was proven by sterol measurement in hair - in control animals lathosterol and cholesta-7,24-dien-3β-ol, the target molecules of SC5D in the sterol biosynthetic pathways, together constituted a mean of 10% of total sterols; in the conditional knockout mice these sterols constituted a mean of 56% of total sterols. The constitutive knockout mice had an even greater increase, with lathosterol and cholesta-7,24-dien-3β-ol accounting for 80% of total sterols. In conclusion, the dominant presence of the 7-DHC precursors in hair of conditional animals and the lack of increased circulating D following exposure to UVR reflect attenuated production of the D photochemical precursor 7-DHC and, consequently, of D itself. These animals provide a useful new tool for investigating the role of D in UVR-induced physiological effects and, more broadly, for investigations of the cholesterol synthetic pathway in the skin and other targeted tissues.