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

Table 1

Genetic factors related to vitamin D and primary biliary cirrhosis.

	Primary biliary cirrhosis (PBC)	Vitamin D
Human leukocyte antigen (HLA)	HLA-DR expression increased in patients with PBC [24–31]	Calcitriol suppresses MHC class II antigen expression in human mononuclear phagocytes and decreases interferon-γ-induced HLA-DR antigen expression in normal and transformed human keratinocytes [32–35]
Vitamin D receptor (VDR)	(i) BsmI polymorphisms of VDR were associated with PBC in German, Hungarian, Japanese, Italian, and Chinese patients [36–40]
	(ii) In the Polish population, BsmI and TaqI polymorphisms were associated with the presence of advanced fibrosis/liver cirrhosis at the diagnosis of PBC [41]
	(iii) VDR polymorphisms predicted a decreased bone mineral density in PBC patients [42, 43]
Toll-like receptors (TLRs)	(i) The expression of TLR-3 was markedly increased in biliary epithelial cells (BECs) in areas of ductular reaction in liver diseases, including PBC [45]	(i) Calcitriol has been shown to down-regulate intracellular TLR-2, TLR-4, and TLR-9 expression in human monocytes [55]
	(ii) The bile duct epithelial cells in PBC liver tissues markedly expressed TLR-4, which was also observed in periportal hepatocytes of PBC liver tissues and its expression was extended to interlobular hepatocytes in advanced-stage PBC [47]	(ii) TLR activation results in the expression of the VDR and 1α-vitamin D hydroxylase in human monocytes [56]
		(iii) Biliary epithelial cells show intense immune reactivity for cathelicidin and for VDR [59]
Apolipoprotein E (ApoE)	(i) The ApoE ε4 allele was suggested as a marker of disease severity in PBC [63]	(i) The LDL receptor on calcitriol-induced macrophages has been found to exhibit specificity for ApoB- and ApoE-containing lipoproteins [67]
	(ii) The ε4 allele carriers demonstrated a poor response to ursodeoxycholic acid (UDCA) treatment [64]	(ii) Among ApoE knockout mice, those with dyslipidemia, high oxidative stress, and pronounced atherosclerosis after unilateral nephrectomy developed less plaque growth and calcification with vitamin D analog treatment (paricalcitol) [60–68]
Nramp1	Novel alleles at a polymorphic microsatellite repeat region in the human NRAMP1 gene promoter were identified in patients with PBC [32]	Calcitriol is known to stimulate phagocytosis and affects NRAMP1 transcription and protein expression in maturing phagocytes [78]
Cytotoxic T lymphocyte antigen-4 (CTLA-4)	(i) PBC is known to be associated with polymorphisms of the CTLA-4 gene in Chinese, Japanese, Canadian, French, American Caucasian, and British patients but not in Brazilian patients [80–86]; (ii) The meta-analysis suggests that the CTLA-4 gene may be a risk factor for PBC in Asians, while the AA genotype may be negatively associated with PBC [87–89]	Calcitriol promoted regulatory T-cell profiles by increasing CTLA-4 and interleukin-10 in mouse colon protein extracts and stimulated the expression of high levels of CTLA-4 in human CD4^+ CD25^− T cells [95, 96]