Vitamin D inhibits proliferation and profibrotic marker expression in hepatic stellate cells and decreases thioacetamide-induced liver fibrosis in rats

Shirley Abramovitch, Liora Dahan-Bachar, Efrat Sharvit, Yosef Weisman, Amir Ben Tov, Eli Brazowski, Shimon Reif

Research output: Contribution to journalArticlepeer-review

Abstract

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.

Original languageEnglish
Pages (from-to)1728-1737
Number of pages10
JournalGut
Volume60
Issue number12
DOIs
StatePublished - Dec 2011

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