## 4 Skin Biology, Vitamin D Synthesis, and Its Impacting Factors
### Synthesis and Metabolism of Vitamin D in Human Skin  
Pre-vitamin D3 is created via a photochemical reaction involving provitamin D3, also known as 7-dehydrocholesterol (7-DHC), which is a precursor mostly present in the basal and spinous cell layers of the skin's epidermis [121]. More specific to this is the stratum basale, comprising stem and transient amplifying cells that generate the upper cells, which in turn produce keratins K5 and K15 and proliferation markers such as \(\beta\)-catenin (CTNNB), cyclin D1, and the GLI1 gene. After migrating to the spinous layer, the cells produce different keratins, namely K1 and K10, as well as enzymes and precursors implicated in cornified envelope formation, namely involucrin and transglutaminase-K. Filaggrin and loricrin protein expressions mark the beginning of further migration into the stratum granulosum, thus contributing to cornified envelope generation. Such cells additionally partake in lipid production, including lipids packaged into lamellar bodies, and are injected into the intracellular spaces between the stratum granulosum and stratum corneum with a view to waterproof the permeability barrier. Interestingly, lamellar bodies contain antimicrobial peptides like cathelicidin formulated in the stratum granulosum, providing protection against invasive organisms. _VDR_ and CYP27B1 expression is the highest in the stratum basale, where the mediator of RNA polymerase (MED1) and the steroid receptor coactivator-3 (SRC-3) are two major _VDR_ action coregulators. On the one hand, MED1 expressed mainly in the stratum basale and spinosum facilitates _VDR_'s modulation of proliferation at early stages of differentiation, and stratum granulosum SRC-3 accelerates the _VDR_'s regulation of terminal differentiation [122]. Along with its effects on the kidneys, calcitriol bound to the vitamin D binding protein also affects target organs that express _VDR_s, such as the bone, gut, and parathyroid (PTH) gland, via both genomic and non-genomic pathways. Geographical, seasonal, and environmental factors including pollution, sun exposure, month, location, or altitude heavily affect the amount of vitamin D generated and the time required for this procedure [123]. Under the predominant impact of UVB radiation (280-320 nm), 7-DHC is quickly converted to pre-vitamin D3 (pre-D3) in the skin, and then pre-D3 rearranges under heat (thermal) exposure to generate vitamin D3. By converting pre-D3 into the physiologically inert substances tachysterol and lumisterol through continued UVB exposure, harmful D3 buildup is avoided. Lumisterol and tachysterol are reverted back to pre-D3 in dark conditions (Figure 5) [30]. Thus, skin pigmentation and UV intensity impact this process; melanin absorbs UV radiation, lowering the efficiency of D3 generation in people with darker skin, which helps explain why these target groups demonstrate lower 25(OH)D3 levels in clinical tests [124]. At the end of this procedure, vitamin D3 enters the bloodstream and is transported to the liver, after binding to the _VDR_[30,121]. Skin pigmentation is influenced by the melanin pigment, as well as seasonal aspects, UVR's impact, taming, and genetic adaptation capabilities. Direct skin sun exposure to sun rays and the need to improve thermoregulation also led humans to gradually evolve the skin pigment over time. Interestingly, skin pigmentation not only acts as a shield against UVR damage, but also as an important defensive mechanism against heat dissipation and vitamin D deficiency, and thus, an evolutionary balancing aspect between vitamin D synthesis, vitamin D's activities, and UVR protection [125]. Seasonal differences may also have an impact on D3 production in areas far from the equator; vitamin D3 levels affected by melanin's activity are higher during summer, and lower during winter levels.