The Role of Vitamin D in Primary Biliary Cirrhosis: Possible Genetic and Cell Signaling Mechanisms

Table 2

Summary of the cell signaling mechanisms to Vitamin D primary biliary cirrhosis.

	Primary biliary cirrhosis	Vitamin D
The matrix metalloproteinases (MMPs)	(i) Mdr2^−/− mice develop hepatic lesions resembling primary sclerosing cholangitis and spontaneously progress to severe fibrosis accompanied by the upregulation of MMP-2, MMP-13, and TIMP-1 [97]	(i) VDR knockout mice had increased MMP-2, MMP-9, and MMP-12 in the lung [102]
	(ii) Increased serum MMP-1 and -2 were observed in patients with PBC [98–100]	(ii) The VDR TaqI polymorphism is associated with the decreased production of TIMP-1 [103]
	(iii) Polymorphism of MMP-3 influences susceptibility to primary sclerosing cholangitis [101]	(iii) Calcitriol modulates tissue MMP expression under experimental conditions and downregulates MMP-9 levels in keratinocytes [104]
Prostaglandins (PGs)	(i) Phytohemagglutinin-stimulated enriched monocytes from PBC patients produced approximately threefold more PG E2 than did normal control monocytes and alcoholic cirrhosis monocytes [112]; (ii) PBC epithelial cells showed moderate levels of COX-2 expression [115]	Calcitriol regulates the expression of several key genes involved in PG pathways [116]
Reactive oxygen species (ROS)	(i) Lipid peroxidation markers, such as plasma and urinary 8-isoprostane and plasma malondialdehyde (MDA), were significantly increased, whereas plasma total glutathione (GSH) levels reduced in patients with PBC [119]	Vitamin D reduces ROS [123–128]
	(ii) Ursodeoxycholic acid (UCDA) treatment partially corrected plasma GSH status in patients with PBC [120]
Transforming growth factor β (TGF-β)	(i) TGF-β 3 was overexpressed in hepatocytes in PBC patients [133]; (ii) TGF-β pathway signaling was identified in the biliary endothelial cells of patients with posttransplantation recurrence of PBC [136]; (iii) TGF-β levels were also reported to increase in the bone marrow mononuclear cells of PBC patients compared with autoimmune hepatitis type 1 patients [137, 138]; (iv) UCDA treatment reduced TGF-β levels in patients with PBC [139]	(i) TGF-β levels correlated negatively with vitamin D levels; namely, increased TGF-β 1 and platelet counts are an early indicator of bone marrow fibrosis in patients with vitamin D deficiency [141]; (ii) Calcitriol reduces TGF-β 3-induced fibrosis-related gene expression in human leiomyoma cells [144]; (iii) Vitamin D treatment significantly down-regulated the free fatty acids-induced expression of TGF-β in HSC line LX-2 [145]