Abstract
The 3β-hydroxysterol Δ14-reductase, encoded by the Tm7sf2 gene, is an enzyme involved in cholesterol biosynthesis. Cholesterol and its derivatives control epidermal barrier integrity and are protective against environmental insults. To determine the role of the gene in skin cholesterol homeostasis, we applied 12-o-tetradecanoylphorbol-13-acetate (TPA) to the skin of Tm7sf2+/+ and Tm7sf2-/- mice. TPA increased skin cholesterol levels by inducing de novo synthesis and up-take only in Tm7sf2+/+ mouse, confirming that the gene maintains cholesterol homeostasis under stress conditions. Cholesterol sulfate, one of the major players in skin permeability, was doubled by TPA treatment in the skin of wild-type animals but this response was lost in Tm7sf2-/- mice. The expression of markers of epidermal differentiation concomitant with farnesoid-X-receptor and p38 MAPK activation were also disrupted in Tm7sf2-/- mice. We then subjected Tm7sf2+/+ and Tm7sf2-/- mice to a classical two-stage skin carcinogenesis protocol. We found that the loss of Tm7sf2 increased incidence and multiplicity of skin papillomas. Interestingly, the null genotype showed reduced expression of nur77, a gene associated with resistance to neoplastic transformation. In conclusion, the loss of Tm7sf2 alters the expression of proteins involved in epidermal differentiation by reducing the levels of cholesterol sulfate.
Highlights
The 3b-hydroxysterol D14-reductase, encoded by the Tm7sf[2] gene, is an enzyme involved in cholesterol biosynthesis
Cholesterol and/or its derivatives may play a direct role in epidermal homeostasis and TPA is known to change the metabolism of sterols in mouse skin[17]
We found that TPA induced a decrease in Abca[1] expression in both genotypes (Figure 1B), whereas it induced a significant increase in the mRNA levels of both hydroxy-3-methylglutaryl-CoA reductase (Hmgcr) and low density lipoprotein receptor (Ldlr) only in the skin of Tm7sf21/1 mice (Fig. 1C and D)
Summary
Tm7sf[2] gene drives cholesterol accumulation after TPA exposure. Cholesterol and/or its derivatives may play a direct role in epidermal homeostasis and TPA is known to change the metabolism of sterols in mouse skin[17]. To determine whether the loss of the Tm7sf[2] gene can cause decreased expression of the Sult2B1 gene, we analyzed its expression up to 8 h TPA treatment and found that TPA induced a significant increase in Sult2B1 mRNA levels only in the Tm7sf21/1 mouse skin (Fig. 2B). These data indicate that the Tm7sf[2] gene regulates CS biosynthesis by increasing cholesterol levels and the expression of an enzyme involved in cholesterol sulfonation. These results demonstrate that loss of Tm7sf[2] markedly increases size, incidence and multiplicity of skin papillomas
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