TY - JOUR
T1 - Vitamin D inhibits proliferation and profibrotic marker expression in hepatic stellate cells and decreases thioacetamide-induced liver fibrosis in rats
AU - Abramovitch, Shirley
AU - Dahan-Bachar, Liora
AU - Sharvit, Efrat
AU - Weisman, Yosef
AU - Tov, Amir Ben
AU - Brazowski, Eli
AU - Reif, Shimon
PY - 2011/12
Y1 - 2011/12
N2 - Background and aim: Hepatic stellate cells (HSCs) are key participants in liver fibrosis development. 1,25 (OH) 2D 3, the active form of vitamin D, has antiproliferative properties and antifibrotic potential, as well as a role in extracellular matrix and matrix metalloproteinase (MMP) regulation in renal and lung fibrosis. Little is known about the role of 1,25(OH) 2D 3 in liver and its involvement in liver fibrosis. Therefore, we investigated the antiproliferative and antifibrotic effects of 1,25(OH) 2D 3 in primary cultured HSCs and in a rat model of liver fibrosis induced by thioacetamide (TAA). Methods: Primary HSCs were isolated from rats' livers and treated with 1,25(OH) 2D 3. Proliferation was examined by bromodeoxyuridine. Vitamin D receptor (VDR) expression and several fibrotic markers were detected by western blot analysis and real-time PCR. Collagen Ia1 and MMP-9 promoter activity were measured by luciferase assay. MMP-9 enzymatic activity was investigated by zymography. VDR silencing was performed by sh-RNA. An in vivo study was performed on TAA-induced liver fibrosis model in rats treated with or without 1,25 (OH) 2D 3. The fibrotic score and collagen deposition were determined by Masson and by Sirius red staining. Results: While VDR was highly expressed in quiescent HSCs, its expression decreased up to 40% during activation. Addition of 1,25(OH) 2D 3 to activated HSCs stimulated VDR expression. 1,25(OH) 2D 3 suppressed HSC proliferation and cyclin D1 expression by ∼50% and tissue inhibitor of metalloproteinase 1 (TIMP-1) by 60% and led to a 40% downregulation of collagen Ia1 expression. Moreover, 1,25(OH) 2D 3 increased MMP-9 activity by 30%. Silencing VDR by sh-RNA demonstrated that suppression of cyclin D1 and collagen Iα1 protein expression was VDR dependent. Treatment with 1,25 (OH) 2D 3 significantly reduced extracellular matrix deposition and lowered the fibrotic score in TAA-induced liver fibrosis. Conclusion: 1,25(OH) 2D 3 has antiproliferative and antifibrotic effects on liver fibrosis in in vitro and in vivo models and may be considered as having potential therapeutic value.
AB - Background and aim: Hepatic stellate cells (HSCs) are key participants in liver fibrosis development. 1,25 (OH) 2D 3, the active form of vitamin D, has antiproliferative properties and antifibrotic potential, as well as a role in extracellular matrix and matrix metalloproteinase (MMP) regulation in renal and lung fibrosis. Little is known about the role of 1,25(OH) 2D 3 in liver and its involvement in liver fibrosis. Therefore, we investigated the antiproliferative and antifibrotic effects of 1,25(OH) 2D 3 in primary cultured HSCs and in a rat model of liver fibrosis induced by thioacetamide (TAA). Methods: Primary HSCs were isolated from rats' livers and treated with 1,25(OH) 2D 3. Proliferation was examined by bromodeoxyuridine. Vitamin D receptor (VDR) expression and several fibrotic markers were detected by western blot analysis and real-time PCR. Collagen Ia1 and MMP-9 promoter activity were measured by luciferase assay. MMP-9 enzymatic activity was investigated by zymography. VDR silencing was performed by sh-RNA. An in vivo study was performed on TAA-induced liver fibrosis model in rats treated with or without 1,25 (OH) 2D 3. The fibrotic score and collagen deposition were determined by Masson and by Sirius red staining. Results: While VDR was highly expressed in quiescent HSCs, its expression decreased up to 40% during activation. Addition of 1,25(OH) 2D 3 to activated HSCs stimulated VDR expression. 1,25(OH) 2D 3 suppressed HSC proliferation and cyclin D1 expression by ∼50% and tissue inhibitor of metalloproteinase 1 (TIMP-1) by 60% and led to a 40% downregulation of collagen Ia1 expression. Moreover, 1,25(OH) 2D 3 increased MMP-9 activity by 30%. Silencing VDR by sh-RNA demonstrated that suppression of cyclin D1 and collagen Iα1 protein expression was VDR dependent. Treatment with 1,25 (OH) 2D 3 significantly reduced extracellular matrix deposition and lowered the fibrotic score in TAA-induced liver fibrosis. Conclusion: 1,25(OH) 2D 3 has antiproliferative and antifibrotic effects on liver fibrosis in in vitro and in vivo models and may be considered as having potential therapeutic value.
UR - http://www.scopus.com/inward/record.url?scp=80655127773&partnerID=8YFLogxK
U2 - 10.1136/gut.2010.234666
DO - 10.1136/gut.2010.234666
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C2 - 21816960
AN - SCOPUS:80655127773
SN - 0017-5749
VL - 60
SP - 1728
EP - 1737
JO - Gut
JF - Gut
IS - 12
ER -
