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.

Vitamin D-induced up-regulation of human keratinocyte cathelicidin anti-microbial peptide expression involves retinoid X receptor α

“…Summarized data are presented as means ± SEM of four to six observations in each group. *P < 0.05, **P < 0.01 for the comparisons indicated by the horizontal line; **P < 0.01, ***P < 0.001 vs. NC in the absence of 1,25D3 Consiglio et al (2015) have recently shown that treatment of HaCaT cells with 10 and 100 nM 1,25D3 for 24 h has no effect on VDR protein expression as assessed by western blotting of nuclear extracts of HaCaT cells. Taken together, these data suggest that a rather long (more than 24 h) stimulation with 1,25D3 is needed to observe a reduction of the VDR protein level in HaCaT cells.…”

Vitamin D regulation of a SOD1-to-SOD2 antioxidative switch to prevent osteosarcoma transformation

“…These proteins are subunits of cytochrome c oxidase complex IV part of the active mitochondrial respiratory chain and contribute to the proton electrochemical gradient across the inner mitochondrial membrane. Previous studies have shown that both of these subunits were inhibited after 1,25D 3 treatment in skin keratinocyte models 36 , and may be involved in osteosarcoma. However, after both 10nM and 100nM 1,25D 3 and VAZ co-treatments of MG-63 cells for 24 and 48 hours, no striking differences in the gene expression of both COXII and COX4I1 were observed ( Figure 3A,B ).…”

“…In all cell types it was found that upon VDR ablation there was an increase in respiration and ROS production associated with elevations in both mitochondrial COX2 and nuclear COX4I1 42 . On the other hand, 1,25D 3 treatment of skin keratinocytes resulted in decreased COX2 and COX4I1 mRNA levels, suggesting a concomitant reduction in intracellular ROS production 36 . Although in this study, evidence was provided for a mitochondrial-specific antioxidant effect of vitamin D within MG-63 cells, no change in either COX2 or COX4I1 transcript levels was found ( Figure 3A,B ).…”

Mitochondrial Hormone Receptors - an Emerging Field of Signaling in the Cell’s Powerhouse

“…The p43 protein was shown to stimulate mitochondrial gene expression and to influence cell differentiation and apoptosis [16], whereas the role of p28 remains to be identified. The vitamin D 3 receptor (VDR) was also detected in mitochondria [17][18][19][20][21]. VDR translocation was reported to take place via the permeability transition pore [18].…”

“…VDR translocation was reported to take place via the permeability transition pore [18]. VDR signaling seems to mainly result in the suppression of respiratory activity [19][20][21]. Additional effects on lipid metabolism have been discussed.…”