The normal liver harbors the vitamin D nuclear receptor in nonparenchymal and biliary epithelial cells

Abstract

The liver is generally considered negative for the vitamin D nuclear receptor (VDR n ), even though several studies have shown significant effects of 1,25-dihydroxyvitamin D 3 (1,25(OH) 2 D 3 ) on liver cell physiology. The low abundance of VDR n in the liver led us to propose that hepatocytes (the largest hepatic cell population) were most likely negative for the receptor, whereas the small hepatic sinusoidal and ductular cell populations that contain cell types known to express VDR n in other tissues should express the receptor. Using freshly isolated cells from normal livers as well as biliary and epithelial hepatic cell lines, our data show that the human, rat, and mouse hepatocytes express very low VDR n messenger RNA (mRNA) and protein levels. I t is generally recognized that the liver is largely negative for the vitamin D nuclear receptor (VDR n ), although estrogens have been shown to induce the appearance of the VDR n in male and female rat livers 1 and Sandgren et al. 2 reported the presence of a very low VDR n density in normal rat livers (1,300-fold lower than in intestine). Segura et al. 3 recently reported that fetal, neonatal, and adult rat hepatocytes show nuclear immunoreactivity for the VDR n , although the specificity of the labeling observed was not entirely clear.Experimental evidence indicates that the vitamin D 3 (D 3 ) hormone 1,25-dihydroxyvitamin D 3 (1,25(OH) 2 D 3 ) has selective activity in the liver. Baran et al. 4,5 have shown that 1,25(OH) 2 D 3 increases intracellular Ca 2ϩ in rat hepatocytes, although the mode of action of the hormone in these studies may be due to a membrane receptor rather than the VDR n . 6 Studies performed in our laboratory 7,8 as well as by Whitfield et al. 9,10 indicate that the liver responds to 1,25(OH) 2 D 3 , as indicated by its control of DNA polymerase ␣ activity as well as cytoplasmic and nuclear protein kinases leading to an accelerated regeneration process following two-thirds partial hepatectomy in the rat. The latter observations suggest that 1,25(OH) 2 D 3 has a significant effect on liver cell physiology during the compensatory growth process. In addition, the hormone has been reported as an inhibitor of the D 3 -25 hydroxylase 11,12 and a significant modulator of the gene encoding the mitochondrial D 3 -25/cholesterol/bile acid hydroxylase (CYP27A). 13 However, the hormone mode of action during these experimental paradigms has not been investigated and the presence of the VDR n in liver cells still remains an open question. The absence or extremely low level of VDR n reported to date in liver led us to propose that hepatocytes, which constitute the largest hepatic cell population, were most

Vitamin D levels and liver histological alterations in children with nonalcoholic fatty liver disease

“…A possible role for VD in liver fibrosis is supported by the fact that VDR is expressed in hepatic stellate cells (HSCs) (31). Such cells play a critical role in the pathogenesis of liver fibrosis, as they are responsible for the deposition of extracellular matrix (ECM) proteins.…”

Retinoids induce cytochrome P450 3A4 through RXR/VDR-mediated pathway

“…Furthermore, the level of VDR is much higher (>20-fold) in mouse than in human or rat hepatocytes [35]. Using VDR knockout mice might provide a direct evidence for the role of VDR in regulating Cyp3a11 gene expression.…”

Modulation of Bile Acid Metabolism by 1α-Hydroxyvitamin D3Administration in Mice

“…1,25(OH) 2 D 3 increases plasma bile clearance of vitamin D 3 and 1,25(OH) 2 D 3 (Gascon-Barré and Gamache, 1991). Whereas hepatocytes express low levels of VDR, biliary epithelial cells express functional VDR (Gascon-Barré et al, 2003). VDR activation in biliary epithelial cells may influence biliary excretion of bile acids as well as that of vitamin D compounds.…”

“…Expression of enzymes (Cyp8b1 and Cyp3a11) and transporters (Ntcp, Oapt1a1, Oatp1a4, Oatp1b2, Bsep, Mrp2, Mrp3, Mrp4, and Ost␤) was not significantly changed (data not shown). Because VDR does not induce transcription of a target gene in hepatocytes because of low expression of VDR (Gascon-Barré et al, 2003) mRNA expression of Cyp24a1 in the kidney and small intestine (Fig. 8,B and C), indicating that 1␣(OH)D 3 treatment effectively activates VDR in these tissues.…”