Vitamin D inhibits development of liver fibrosis in an animal model but cannot ameliorate established cirrhosis

Abstract

1,25(OH)2D3, the active form of vitamin D, has an antiproliferative and antifibrotic effect on hepatic stellate cells. Our aim was to investigate the potential of 1,25(OH)2D3 to inhibit the development of liver fibrosis and to ameliorate established fibrosis in vivo. The antifibrotic effect of 1,25(OH)2D3 was investigated in a thioacetamide (TAA) model (as a preventive treatment and as a remedial treatment) and in a bile duct ligation model. In the preventive model, rats received simultaneously intraperitoneum injection of TAA and/or 1,25(OH)2D3 for 10 wk. In the remedial model, rats were treated with TAA for 10 wk and then received 1,25(OH)2D3 or saline for 8 wk. Fibrotic score was determined by Masson staining. Collagen I, α-smooth muscle actin (α-SMA), tissue inhibitor of metalloproteinase-1 (TIMP1), platelet-derived growth factor (PDGF), and transforming growth factor-β (TGF-β) expression were measured by Western blot analysis and real-time PCR. Hypercalemia was detected by chemistry measurements. Preventive treatment of 1,25(OH)2D3 significantly suppressed liver fibrosis both macroscopically and microscopically and significantly lowered the fibrotic score of the TAA + 1,25(OH)2D3 group compared with the TAA group. 1,25(OH)2D3 significantly inhibited expression of PDGF and TGF-β by ∼50% and suppressed the expression of collagen Iα1, TIMP1, and α-SMA by approximately three-, two-, and threefold, respectively. In contrast, 1,25(OH)2D3 was inefficient in amelioration of established liver fibrosis. Administration of 1,25(OH)2D3 to bile duct ligation rats led to a high mortality rate probably caused by hypercalcemia. We conclude that 1,25(OH)2D3 may be considered as a potential preventive treatment in an in vivo model but failed to ameliorate established cirrhosis.

Docosahexanoic Acid Plus Vitamin D Treatment Improves Features of NAFLD in Children with Serum Vitamin D Deficiency: Results from a Single Centre Trial

“…For example, Zhu et al reported that long-term vitamin D deficiency can provoke chronic liver inflammation, inducing apoptosis and activation of hepatic stellate cells (HSC) to initiate liver fibrosis [41]. There is also evidence indicating that vitamin D is able to modulate HSC activation in vitro and to reduce liver fibrosis in experimental models of liver injuries [21,33]. Despite a clear and marked improvement in the NAS, there was only a non significant trend toward an improvement in fibrosis score.…”

“…Furthermore, emerging evidence suggests a role for VDD in fibrogenesis, with the potential therefore for an anti-fibrotic effect of vitamin D treatment [20]. The available data to date suggests that vitamin D may reduce fibrotic processes inhibiting the expression of transforming growth factor beta (TGF-β) and suppressing the deposition of collagen Iα1 and the activation of alpha-smooth muscle actine (α-SMA) positive HSCs [21]. …”

Non-alcoholic fatty liver disease connections with fat-free tissues: A focus on bone and skeletal muscle

“…If cross-sectional studies support the potential influence of vitamin D status on NAFLD[50], limited evidence exists proving the effectiveness of vitamin D supplementation in NAFLD patients[51,52]. However, findings from animal models revealed that vitamin D interferes with the activation of hepatic stellate cell, which are responsible for collagen deposition and extracellular matrix remodeling, leading to fibrosis[53]. Vitamin D seems to inhibit hepatic stellate cell proliferation[53], and clinical trials are needed to demonstrate that vitamin D supplementation could slow down the progression from NAFLD to NASH.…”

“…However, findings from animal models revealed that vitamin D interferes with the activation of hepatic stellate cell, which are responsible for collagen deposition and extracellular matrix remodeling, leading to fibrosis[53]. Vitamin D seems to inhibit hepatic stellate cell proliferation[53], and clinical trials are needed to demonstrate that vitamin D supplementation could slow down the progression from NAFLD to NASH. Vitamin D is well known to exert pleiotropic effects.…”

Vitamin D and liver fibrosis: let's start soon before it's too late

“…6 Noteworthy, in a recent study published by Gut, Beilfuss et al 7 basically incontrovertibly demonstrated the antifibrotic effect of Vitamin D in liver fibrosis providing additional support to previous pivotal studies. [8][9][10] In fact, a previous experimental study, using an in vitro model of primary HSCs, showed that 1,25(OH) 2 D 3 may exert an antiproliferative effect by suppressing cyclin D1 expression. 8 Moreover, the same study reported that 1,25(OH) 2 D 3 may exert its antifibrotic activity by affecting collagen Iα1 at three different regulatory levels: inhibition of collagen Iα1 promoter activity, suppression of collagen Iα1 mRNA expression and inhibition of collagen Iα1 protein expression.…”