25(OH) D3 alleviate liver NK cytotoxicity in acute but not in chronic fibrosis model of BALB/c mice due to modulations in vitamin D receptor.

Publisher: BioMed Central Country of Publication: England NLM ID: 100968547 Publication Model: Electronic Cited Medium: Internet ISSN: 1471-230X (Electronic) Linking ISSN: 1471230X NLM ISO Abbreviation: BMC Gastroenterol Subsets: MEDLINE

Original Publication: London : BioMed Central, [2001-

Calcifediol/*pharmacology ; Killer Cells, Natural/*drug effects ; Liver/*drug effects ; Liver Cirrhosis/*drug therapy ; Receptors, Calcitriol/*metabolism ; Vitamins/*pharmacology; Acute Disease ; Animals ; Biomarkers/metabolism ; Calcifediol/metabolism ; Calcifediol/therapeutic use ; Calcium/metabolism ; Chronic Disease ; Killer Cells, Natural/metabolism ; Liver/metabolism ; Liver/pathology ; Liver Cirrhosis/metabolism ; Liver Cirrhosis/pathology ; Male ; Mice ; Mice, Inbred BALB C ; Vitamins/metabolism ; Vitamins/therapeutic use

Background: Low 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 CCl 4 fibrosis model following 25(OH) D3 injections.
Methods: Carbon-tetrachloride (CCl 4 ) 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.
Results: Systemic inflammation and hepatic-fibrosis increased along 4 weeks of CCl 4 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 CCl 4 . 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 CCl 4 did not affect pHSCs killing and fail to reduce fibrosis.
Conclusion: Vitamin 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.

Endocr Rev. 1982 Fall;3(4):331-66. (PMID: 6295752)
Eur J Gastroenterol Hepatol. 2018 Jul;30(7):741-746. (PMID: 29664746)
Hepatology. 2008 Sep;48(3):963-77. (PMID: 18726940)
Dig Liver Dis. 2019 Jul;51(7):1036-1042. (PMID: 30683615)
Calcif Tissue Int. 2013 Feb;92(2):77-98. (PMID: 22782502)
Cell. 2013 Apr 25;153(3):601-13. (PMID: 23622244)
Biomed Pharmacother. 2019 Jan;109:1351-1360. (PMID: 30551386)
Sci Signal. 2009 Jun 16;2(75):re4. (PMID: 19531804)
Curr Med Res Opin. 2008 Jan;24(1):139-49. (PMID: 18034918)
J Viral Hepat. 2019 Jun;26(6):774-777. (PMID: 30739371)
Genet Mol Res. 2015 Feb 06;14(1):981-8. (PMID: 25730037)
Gastroenterology Res. 2018 Aug;11(4):309-316. (PMID: 30116431)
Nutr Rev. 2008 Oct;66(10 Suppl 2):S73-87. (PMID: 18844850)
Gut. 2011 Dec;60(12):1728-37. (PMID: 21816960)

Keywords: Hepatic fibrosis; Hypercalcemia; NK cells; Vitamin D receptor

0 (Biomarkers)
0 (Receptors, Calcitriol)
0 (Vdr protein, mouse)
0 (Vitamins)
P6YZ13C99Q (Calcifediol)
SY7Q814VUP (Calcium)

Date Created: 20200412 Date Completed: 20210114 Latest Revision: 20210114

20221213

PMC7149903

10.1186/s12876-020-01248-5

32276660