Biotin Is Required for the Zinc Homeostasis in the Skin

Abstract

Patients with biotin deficiency present symptoms that are similar to those in patients with acrodermatitis enteropathica (inherent zinc deficiency). However, the association between biotin and zinc deficiency remains unknown. We have previously shown that epidermal keratinocytes of mice fed zinc-deficient (ZD) diets secreted more adenosine triphosphate (ATP) than those of mice fed zinc-adequate (ZA) diets and that epidermal Langerhans cells are absent in ZD mice. Langerhans cells highly express CD39, which potently hydrolyzes ATP into adenosine monophosphate (AMP). Thus, a lack of Langerhans cells in ZD mice leads to non-hydrolysis of ATP, thereby leading to the development of ATP-mediated irritant contact dermatitis. In this study, we examined if biotin-deficient (BD) mice showed the same underlying mechanisms as those in ZD mice. BD mice showed reduced serum zinc levels, disappearance of epidermal Langerhans cells, and enhanced ATP production in the skin. Consequently, irritant contact dermatitis was significantly enhanced and prolonged in BD mice. In conclusion, the findings of our study showed that biotin deficiency leads to zinc deficiency because of which patients with biotin deficiency show similar symptoms as those with acrodermatitis enteropathica.

Keywords: Langerhans cells; acrodermatitis enteropathica; adenosine triphosphate; biotin deficiency; zinc deficiency.

Figure 1

(A) Five-week-old female BALB/c mice were fed biotin-adequate (BA) (control diet) or biotin-deficient (BD) diet for 12 weeks. (B) Serum zinc levels of zinc-adequate (ZA) and zinc-deficient (ZD) mice after consumption of ZA (control) and ZD diet for seven weeks (left panel). Serum zinc levels of BA and BD mice fed BA (control) and BD diets for the indicated weeks (right panel). Five mice of each group were analyzed. Course of body weight (C) and survival rate (D) of BA and BD mice. Ten mice of each group were analyzed. (E) Change of skin phenotype of BA and BD mice after consumption of BA and BD diets for the indicated weeks (hematoxylin and eosin stain, ×100). Data are representative of three independent experiments. * p < 0.05, ** p < 0.01.

Figure 2

(A,B) Five-week-old female BALB/c mice were fed BA (control diet) or BD diet for 12 weeks. Epidermal langerhans cells (LCs) were identified as CD45⁺IA/IE⁺ cells. Three mice for each group were analyzed. (C) ATP release in response to BAC from the ear skins of BA and BD mice at 12 weeks after the initiation of BA and BD diets. Five mice of each group were analyzed. (D) ACD (left panel) and ICD (right panel) in BA and BD mice at 12 weeks after the initiation of BA and BD diets. Five mice of each group were analyzed. (E,F) ears of BA and BD mice elicited irritant contact dermatitis (ICD) response at 24 h after CrO application. (G) mRNA expression of molecules associated with LC differentiation and survival in KCs. Data are representative of 3 independent experiments. * p < 0.05, ** p < 0.01, *** p < 0.001.