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

Pediatric Gastroenterology Unit, Tel-Aviv Medical Center, Tel-Aviv, Israel.
Gut (Impact Factor: 14.66). 08/2011; 60(12):1728-37. DOI: 10.1136/gut.2010.234666
Source: PubMed


Hepatic stellate cells (HSCs) are key participants in liver fibrosis development. 1,25(OH)(2)D(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)(2)D(3) in liver and its involvement in liver fibrosis. Therefore, we investigated the antiproliferative and antifibrotic effects of 1,25(OH)(2)D(3) in primary cultured HSCs and in a rat model of liver fibrosis induced by thioacetamide (TAA).
Primary HSCs were isolated from rats' livers and treated with 1,25(OH)(2)D(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 Iα1 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)(2)D(3). The fibrotic score and collagen deposition were determined by Masson and by Sirius red staining.
While VDR was highly expressed in quiescent HSCs, its expression decreased up to 40% during activation. Addition of 1,25(OH)(2)D(3) to activated HSCs stimulated VDR expression. 1,25(OH)(2)D(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 Iα1 expression. Moreover, 1,25(OH)(2)D(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)(2)D(3) significantly reduced extracellular matrix deposition and lowered the fibrotic score in TAA-induced liver fibrosis.
1,25(OH)(2)D(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.

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    • "Recent compelling studies demonstrate that vitamin D inhibits the nuclear factor-í µí¼…í µí»½ (NF-í µí¼…í µí»½) pathway directly regulating genes that contribute to cell proliferation, inflammation, fibrogenesis , increased oxidative stress, and decreased MMP-9 (as discussed by [69]). Experiments in rats showed that vitamin D reduced ECM deposition in induced liver fibrosis and lowered the fibrotic score in the animals (as discussed by [70]). "
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    Obstetrics and Gynecology International 07/2014; 2014:783289. DOI:10.1155/2014/783289
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    • "Another report demonstrated the presence of VDR mRNA and protein in the livers of rats throughout life [15]. Both in vitro and in vivo models have demonstrated anti-proliferative and anti-fibrotic effects of calcitriol on liver fibrosis [16]. In concanavalin A (ConA)-induced mouse AIH, calcitriol significantly decreased the serum alanine transaminase (ALT) levels and markedly attenuated histological liver damage. "
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    ABSTRACT: Autoimmune hepatitis is an inflammation of the liver characterized by the presence of peri-portal hepatitis, hypergammaglobulinemia, and the serum autoantibodies. The disease is classified into 2 distinct types according to the nature of auto-antibodies. Disturbances of the calcium-parathyroid hormone-vitamin D axis are frequently associated with chronic liver disease. Patients with AIH have a high prevalence of vitamin D deficiency. Genetic studies have provided the opportunity to determine which proteins link vitamin D to AIH pathology, namely, the major histocompatibility complex class II molecules, vitamin D receptors, toll-like receptors, cytotoxic T lymphocyte antigen-4, cytochrome P450 CYP2D6, regulatory T cells (Tregs) and the forkhead/winged helix transcription factor 3. Vitamin D also exerts its effect on AIH through non-genomic factors, namely, mitogen-activated protein kinase signaling pathways, γδT cells, interferon-gamma nitric oxide synthase, and reactive oxygen stress. In conclusion, vitamin D may have a beneficial role in AIH and improves liver function in concanavalin A-induced mouse AIH. Calcitriol is best used for AIH because it is the active form of a vitamin D3 metabolite and its receptors are present in sinusoidal endothelial cells, Kupffer cells, stellate cells of normal livers, and the biliary cell line.
    Journal of Clinical Medicine Research 12/2013; 5(6):407-415. DOI:10.4021/jocmr1505w
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    • "It has been suggested that proliferating cholangiocytes play a key role in chronic cholestasis liver diseases that are characterized by biliary fibrosis [19]. Calcitriol protects liver cells during cholestasis by inhibiting CYP7A1 mRNA expression and bile acid synthesis [20], and both in vitro and in vivo models have demonstrated calcitriol's antiproliferative and antifibrotic effects on liver fibrosis [21]. Another link of PBC to vitamin D may be the observation that PBC has seasonal variation; there was a marked peak for diagnoses of PBC in the month of June [22]. "
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    ABSTRACT: Primary biliary cirrhosis (PBC) is an immune-mediated chronic inflammatory disease of the liver of unknown etiology. Vitamin D deficiency is highly prevalent in patients with PBC, and many studies have demonstrated the significant effect of calcitriol on liver cell physiology. Vitamin D has antiproliferative and antifibrotic effects on liver fibrosis. Genetic studies have provided an opportunity to determine which proteins link vitamin D to PBC pathology (e.g., the major histocompatibility complex class II molecules, the vitamin D receptor, toll-like receptors, apolipoprotein E, Nramp1, and cytotoxic T lymphocyte antigen-4). Vitamin D also exerts its effect on PBC through cell signaling mechanisms, that is, matrix metalloproteinases, prostaglandins, reactive oxygen species, and the transforming growth factor betas. In conclusion, vitamin D may have a beneficial role in the treatment of PBC. The best form of vitamin D for use in the PBC is calcitriol because it is the active form of vitamin D3 metabolite, and its receptors are present in the sinusoidal endothelial cells, Kupffer cells, and stellate cells of normal livers, as well as in the biliary cell line.
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