title: Mitochondrial and lipogenic effects of vitamin D on differentiating and proliferating human keratinocytes.
abstract: Even in cells that are resistant to the differentiating effects of vitamin D, the activated vitamin D receptor (VDR) can downregulate the mitochondrial respiratory chain and sustain cell growth through enhancing the activity of biosynthetic pathways. The aim of this study was to investigate whether vitamin D is effective also in modulating mitochondria and biosynthetic metabolism of differentiating cells. We compared the effect of vitamin D on two cellular models: the primary human keratinocytes, differentiating and sensitive to the genomic action of VDR, and the human keratinocyte cell line HaCaT, characterized by a rapid growth and resistance to vitamin D. We analysed the nuclear translocation and features of VDR, the effects of vitamin D on mitochondrial transcription and the consequences on lipid biosynthetic fate. We found that the negative modulation of respiratory chain is a general mechanism of action of vitamin D, but at high doses, the HaCaT cells became resistant to mitochondrial effects by upregulating the catabolic enzyme CYP24 hydroxylase. In differentiating keratinocytes, vitamin D treatment promoted intracellular lipid deposition, likewise the inhibitor of respiratory chain stigmatellin, whereas in proliferating HaCaT, this biosynthetic pathway was not inducible by the hormone. By linking the results on respiratory chain and lipid accumulation, we conclude that vitamin D, by suppressing respiratory chain transcription in all keratinocytes, is able to support both the proliferation and the specialized metabolism of differentiating cells. Through mitochondrial control, vitamin D can have an essential role in all the metabolic phenotypes occurring in healthy and diseased skin.
authors.affiliation: Department of Oncology, University of Torino, Italy.
authors.forename: Marco
authors.initials: M
authors.lastname: Consiglio
authors.affiliation: Department of Oncology, University of Torino, Italy.
authors.forename: Marta
authors.initials: M
authors.lastname: Viano
authors.affiliation: Chirurgia Generale e Specialistiche, Banca della Cute, AOU Città della Salute e della Scienza Torino, Italy.
authors.forename: Stefania
authors.initials: S
authors.lastname: Casarin
authors.affiliation: Chirurgia Generale e Specialistiche, Banca della Cute, AOU Città della Salute e della Scienza Torino, Italy.
authors.forename: Carlotta
authors.initials: C
authors.lastname: Castagnoli
authors.affiliation: Department of Oncology, University of Torino, Italy.
authors.forename: Gianpiero
authors.initials: G
authors.lastname: Pescarmona
authors.affiliation: Department of Oncology, University of Torino, Italy.
authors.forename: Francesca
authors.initials: F
authors.lastname: Silvagno
mesh_terms: D002454:Cell Differentiation / Q000187:drug effects / Q000502:physiology; D002460:Cell Line; D049109:Cell Proliferation / Q000187:drug effects / Q000502:physiology; D019069:Cell Respiration / Q000187:drug effects*; D004789:Enzyme Activation; D006801:Humans; D015603:Keratinocytes / Q000187:drug effects* / Q000502:physiology; D050155:Lipogenesis / Q000187:drug effects*; D008928:Mitochondria / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism; D011090:Polyenes / Q000378:metabolism; D021381:Protein Transport / Q000187:drug effects; D018167:Receptors, Calcitriol / Q000235:genetics / Q000378:metabolism*; D014158:Transcription, Genetic / Q000187:drug effects; D015854:Up-Regulation / Q000187:drug effects; D014807:Vitamin D / Q000494:pharmacology*; D065668:Vitamin D3 24-Hydroxylase / Q000235:genetics / Q000378:metabolism; D014815:Vitamins / Q000494:pharmacology*
chemical_list: D011090:Polyenes; D018167:Receptors, Calcitriol; D014815:Vitamins; D014807:Vitamin D; C041573:stigmatellin; C585549:CYP24A1 protein, human; D065668:Vitamin D3 24-Hydroxylase
keywords: keratinocyte; lipid deposition; mitochondria; respiratory chain; vitamin D receptor