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

作者：Makarova Anastasia M; Pasta Saloni; Watson Gordon; Shackleton Cedric; Epstein Ervin H Jr^*

来源：Journal of Steroid Biochemistry and Molecular Biology, 2017, 171: 187-194.

DOI：10.1016/j.jsbmb.2017.03.017

• Vitamin D-3 synthesis
• Lathosterol
• Sterol C5-desaturase (Sc5d)
• Sc5d knockout
• Cre activation
• Sterol analysis
• Hair sterols

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-3). To separate the experimental effects of sunlight and of all forms of D-3, a mouse in which UVR does not produce D-3 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(2) (Cre/estrogen receptor), we generated two lines of transgenic mice. One line has constitutive keratinocyte-specific inactivation of Sc5d (Sc5d(k14KO)). The other line (Sc5d(k14KOi)) has tamoxifen-inducible keratinocyte-specific inactivation of Sc5d.
Mice deleted for keratinocyte Sc5d lose the ability to increase circulating D-3 following UVR exposure of the skin. Thus, unlike in control mice, acute UVR exposure did not affect circulating D-3 level in inducible Sc5d(k14KOi) mice.
Keratinocyte-specific inactivation of Sc5d was proven by sterol measurement in hair - in control animals lathosterol and cholesta-7,24-dien-3 beta-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-3 beta-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-3 following exposure to UVR reflect attenuated production of the D-3 photochemical precursor 7-DHC and, consequently, of D-3 itself. These animals provide a useful new tool for investigating the role of D-3 in UVR-induced physiological effects and, more broadly, for investigations of the cholesterol synthetic pathway in the skin and other targeted tissues.

• 出版日期2017-7