Abstract
BackgroundLow 25-Hydroxy-vitamin-D; “25(OH)-D3” serum and vitamin D receptor (VDR) levels were recently correlated to advanced fibrosis. However, VDR mechanism in liver fibrosis modulations is not well understood. In this study, we aimed to evaluate changes in liver NK cells cytotoxicity due to modulations in VDR in CCl4 fibrosis model following 25(OH) D3 injections.MethodsCarbon-tetrachloride (CCl4) hepatic-fibrosis was induced in BALB/c mice for 1 and 4 weeks as an acute and chronic fibrosis model, respectively. Along 1th to 4th weeks, vitamin D were i.p injected/2x week. Liver were assessed histologically and for proteins quantification for VDR and αSMA expressions. In vitro, potential killing of NK cells were evaluated following co-culture with primary-hepatic-stellate-cells (pHSCs) obtained from BALB/c WT-mice.ResultsSystemic inflammation and hepatic-fibrosis increased along 4 weeks of CCl4 as indicated by serum ALT and αSMA expressions (P < 0.02) as well as histological assessments, respectively. These results were associated with increased NK1.1 activations and hypercalcemia. While vitamin D administrations delayed fibrosis of early stages, vitamin D worsen hepatic-fibrosis of late stages of CCl4. In week 4, no further activations of NK cells were seen following vitamin D injections and were associated with down-expressions of VDR (1.7 Fold, P < 0.004) indicating the inability of vitamin D to ameliorate hepatic fibrosis. In vitro, NK cells from the chronic model of CCl4 did not affect pHSCs killing and fail to reduce fibrosis.ConclusionVitamin D alleviate liver NK cytotoxicity in acute but not in chronic fibrosis model due to modulations in vitamin D receptor and calcium. Hypercalcemia associated with late fibrosis may inhibited VDR levels, however, may not explain the profibrogenic effects of vitamin D.
Highlights
Low 25-Hydroxy-vitamin-D; “25(OH)-D3” serum and vitamin D receptor (VDR) levels were recently correlated to advanced fibrosis
The authors carried out genetic studies in mice which resulted in spontaneous liver fibrosis when one or both Vdr alleles were knocked out, with more severe fibrosis occurred in Vdr−/− animals [15]
In our chronic fibrotic model, serum vitamin D levels was unchanged as compared to with naive vehicle-treated mice (WT) mice and progressions of liver fibrosis were due to inhibitions of VDR in Hepatic stellate cells (HSCs)
Summary
Low 25-Hydroxy-vitamin-D; “25(OH)-D3” serum and vitamin D receptor (VDR) levels were recently correlated to advanced fibrosis. VDR mechanism in liver fibrosis modulations is not well understood. We aimed to evaluate changes in liver NK cells cytotoxicity due to modulations in VDR in CCl4 fibrosis model following 25(OH) D3 injections. Vitamin D is an important prohormone with known effect on calcium homeostasis [1], but recently there is increasing recognition that vitamin D is involved in cell proliferation and differentiation, it has immunomodulatory and anti-inflammatory properties [2]. The transcriptional activity of this receptor is modulated by several ligands, such as steroids, retinoids and other lipid soluble compounds, and by nuclear proteins acting as co-activators and co-repressors [5]. The liganded VDR heterodimerizes with the retinoid X receptor and binds to vitamin D response elements in the promoter of target genes, thereby affecting their transcription. The genomic organization of the VDR at locus 12q13.1 shows that the VDR gene itself is quite large (over 100 kb) and has an extensive promoter region capable of generating multiple tissue-specific transcripts [6]
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