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
Calcidiol insufficiency is highly prevalent in chronic kidney disease (CKD), but the reasons for this are incompletely understood. CKD associates with a decrease in liver cytochrome P450 (CYP450) enzymes, and specific CYP450 isoforms mediate vitamin D 3 C-25-hydroxylation, which forms calcidiol. Abnormal levels of parathyroid hormone (PTH), which also modulates liver CYP450, could also contribute to the decrease in liver CYP450 associated with CKD. Here, we evaluated the effects of PTH and uremia on liver CYP450 isoforms involved in calcidiol synthesis in rats. Uremic rats had 52% lower concentrations of serum calcidiol than control rats (P Ͻ 0.002). Compared with controls, uremic rats produced 71% less calcidiol and 48% less calcitriol after the administration of vitamin D 3 or 1␣-hydroxyvitamin D 3 , respectively, suggesting impaired C-25-hydroxylation of vitamin D 3 . Furthermore, uremia associated with a reduction of liver CYP2C11, 2J3, 3A2, and 27A1. Parathyroidectomy prevented the uremia-associated decreases in calcidiol and liver CYP450 isoforms. In conclusion, these data suggest that uremia decreases calcidiol synthesis secondary to a PTH-mediated reduction in liver CYP450 isoforms. ] deficiency has also been demonstrated in patients with stages 3 and 4 chronic kidney disease (CKD) and in patients who are on dialysis. [1][2][3][4][5][6][7][8] In fact, low serum 25(OH)D 3 is so intimately associated with CRF that in one study, only 29 and 17% of patients with stages 3 and 4 CKD, respectively, had sufficient levels [defined as a serum 25(OH)D 3 concentrations Ͼ75 nmol/L or 30 ng/ml]. 2 A more recent study showed a prevalence of calcidiol insufficiency and deficiency as high as 98% in predialysis patients with a mean GFR of 18.3 ml/min. 4 Prevalence of low serum 25(OH)D 3 was 78 and 89% in two large cohorts of hemodialysis patients 9,10 and 87% in a large cohort of peritoneal dialysis patients. 11 The metabolic consequences of calcidiol defi-
Collectively, the data illustrate that at mid-gestation 1,25(OH)2D3 is fully active in the modulation of all D3-hydroxylases in the human developing intestine. They also show that the detoxifying enzyme CYP3A4 is not only present along the intestinal tract but is also sensitive to 1,25(OH)2D3, indicating that the hormone may be a key element in intestinal development and in the maintenance of the intestinal mucosa integrity in the basal state and in response to damage-inducing agents.
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