Table 1.
The main effects of vitamin D or its analogs on various liver cells*
| Cell type | Main effects |
|---|---|
| Hepatocytes |
A very low level of VDR expression
Expression is induced in NAFLD but decreased in NASH or chronic hepatitis C (8,9)
VDR activation might be associated with lipid accumulation and contribute to steatosis development (8,10) |
| Kupffer cells |
Abundant expression of VDR that exhibits anti-inflammatory effects upon activation:
VDR activation suppresses the LPS-induced inflammation and downregulates IL-6, TNF, and IL-1b expression (2)
VDR activation mitigates inflammatory response in macrophages following ER stress challenge (3) |
| Hepatic stellate cells |
Significant VDR expression
Vitamin D and its analogs exert inhibitory effects on primary murine hepatic cells or human cell lines, possibly through inactivation of TGF-β/Smad signaling (5-7) |
| Cholangiocytes |
High VDR expression with immunoregulatory functions
Ursodeoxycholic acid and vitamin D induce the expression of antimicrobial peptide cathelicidin through a VDR-dependent mechanism (12)
VDR deficiency promotes cholestatic liver injury through disruption of biliary epithelial cell junctions (13)
Vitamin D or its analog ameliorate liver injury through a VDR-independent pathway (16) |
| Liver cancer cells |
VDR is expressed in human liver cancer cell lines and specimens of human HCC (1,22,23)
KLF4 might play a pivotal role in the regulation of VDR expression in HCC (39)
Supplementation with vitamin D or its analogs inhibits the proliferation of cancer cell lines and induces apoptosis through several mechanisms:
disruption of HGF/c-met/ERK pathway due to downregulation of c-met and ERK (23)
increase in E-cadherin and decrease in Akt expression (28)
induction of cell cycle arrest through p27 accumulation (25)
decreased HDAC2 with increased p21 (WAF1/Cip1) expression and subsequent modulation of p53, Bax, DR5, caspase 8, and Bcl-2 protein expressions (26,27)
modulation of TLR7 expression and β-catenin activation (32)
stimulation of TXNIP expression, inactivation of Notch signaling and/or p27(kip1)-dependent suppression of proinflammatory cytokines secretion (34-36) |
| Cholangiocarcinoma | VDR expression in human cholangiocarcinoma tissue specimens (41-43) Treatment with vitamin D or analogs impairs proliferation and induces apoptosis in cultured cells. Proposed mechanisms include induction of cell cycle arrest through regulation of cyclin D1, cyclin D3, CDK4, CDK6, p21, and/or p27 (44-47) VDR dependent downregulation of LCN2 expression (46,47,49) |
*Abbreviations: CDK – cyclin dependent kinase; c-met – tyrosine-protein kinase Met; DR – death receptor; ER – endoplasmic reticulum; ERK – extracellular signal-regulated kinases; HCC –hepatocellular carcinoma; HDAC2 – histone deacetylase 2; HGF – hepatocyte growth factor; IL-6 – interleukin-6; KLF4 – Krüppel-like factor 4; LCN2 – lipocalin 2; LPS – lipopolysaccharide; NAFLD – nonalcoholic fatty liver disease; NASH – nonalcoholic steatohepatitis; Smad – mothers against decapentaplegic homologue; TGF-β – transforming growth factor beta; TLR – toll-like receptor; TNF – tumor necrosis factor; TXNIP – thioredoxin interacting protein; VDR – vitamin D receptor.