Alterations in gene expression in vitamin D‐deficiency: Down‐regulation of liver Cyp7a1 and renal Oat3 in mice

Abstract

The vitamin D-deficient model, established in the C57BL/6 mouse after 8 weeks of feeding vitamin D-deficient diets in the absence or presence of added calcium, was found associated with elevated levels of plasma parathyroid hormone (PTH) and plasma and liver cholesterol, and a reduction in cholesterol 7α-hydroxylase (Cyp7a1, rate-limiting enzyme for cholesterol metabolism) and renal Oat3 mRNA/protein expression levels. However, there was no change in plasma calcium and phosphate levels. Appraisal of the liver revealed an up-regulation of mRNA expressions of the small heterodimer partner (Shp) and attenuation of Cyp7a1, which contributed to hypercholesterolemia in vitamin D-deficiency. When vitamin D-sufficient or D-deficient mice were further rendered hypercholesterolemic with 3 weeks of feeding the respective, high fat/high cholesterol (HF/HC) diets, treatment with 1α,25-dihydroxyvitamin D [1,25(OH) D ], active vitamin D receptor (VDR) ligand, or vitamin D (cholecalciferol) to HF/HC vitamin D-deficient mice lowered the cholesterol back to baseline levels. Cholecalciferol treatment partially restored renal Oat3 mRNA/protein expression back to that of vitamin D-sufficient mice. When the protein expression of protein kinase C (PKC), a known, negative regulator of Oat3, was examined in murine kidney, no difference in PKC expression was observed for any of the diets with/without 1,25(OH) D /cholecalciferol treatment, inferring that VDR regulation of renal Oat3 did not involve PKC in mice. As expected, plasma calcium levels were not elevated by cholecalciferol treatment of vitamin D-deficient mice, while 1,25(OH) D treatment led to hypercalcemia. In conclusion, vitamin D-deficiency resulted in down-regulation of liver Cyp7a1 and renal Oat3, conditions that are alleviated upon replenishment of cholecalciferol.

Activation of vitamin D in the gingival epithelium and its role in gingival inflammation and alveolar bone loss

“…It is long understood that vitamin D maintains bone health, due to its role in the maintenance of calcium homeostasis. Furthermore, in order to maintain a complete deficiency of vitamin D, we used a diet low in calcium, which has been shown not to affect serum calcium levels . While mice with experimental periodontitis that were injected with 25(OH)D 3 showed decreased bone loss, as do CYP27B1 −/− mice, our experiments are the first to demonstrate that a dietary deficiency in vitamin D leads to inflammation and alveolar bone loss.…”

“…Serum samples from the mice at the end of 6 weeks showed that the mice fed a vitamin D‐absent diet exhibited very low levels of 25(OH)D 3 (Figure A). While this diet includes reduced calcium as well, this has been shown to lead to no reduction in serum calcium levels, even up to 8 weeks . Longer depletion of vitamin D would compromise the general health of the mice, potentially confounding the model .…”

“…While this diet includes reduced calcium as well, this has been shown to lead to no reduction in serum calcium levels, even up to 8 weeks. 30 Longer depletion of vitamin D would compromise the general health of the mice, potentially confounding the model. 31 To determine whether this vitamin D deficiency can lead to symptoms associated with periodontal disease, we quantified the alveolar bone in mice fed the vitamin D-deficient diet compared with the vitamin D-replete diet.…”

Noteworthy idiosyncrasies of 1α,25‐dihydroxyvitamin D3 kinetics for extrapolation from mouse to man: Commentary

“…The pharmacokinetics of exogenously administered calcitriol has been investigated in mice (Chow et al, 2013; Quach et al, 2018), rats (Kissmeyer & Binderup, 1991; Paulson & Kenny, 1985), and humans under normal conditions (Bianchi et al, 1999; Brandi, Egfjord, & Olgaard, 2002; Gray et al, 1978; Seeman et al, 1980), and among patients with chronic kidney disease (CKD) (Ardissino et al, 2000; Brandi et al, 2002; Levine & Song, 1996; Salusky et al, 1990; Torregrosa, Campistol, Mas, Montesinos, & Martinez de Osaba, 1996) or cancer (Fakih et al, 2007; Muindi et al, 2009). Exogenously injected calcitriol would trigger changes in CYP27B1 and CYP24A1 enzymes as well as increase calcium absorption via the intestinal calcium channel, TRPV6 (den Dekker et al, 2003; Hoenderop et al, 2001; Meyer et al, 2006; Weber et al, 2001), giving rise to hypercalcemia (Laubenthal et al, 1975).…”

“…The role of VDR in cholesterol metabolism was implicated in mice in vivo ; serum cholesterol levels were slightly, but significantly, elevated in Vdr‐knockout mice (Wang et al, 2009) and vitamin D deficient mice (Quach et al, 2018). The regulatory mechanism of VDR on lowering cholesterol was elucidated by Chow et al (2014) who showed that activated Vdr upregulated liver Cyp7a1 (the rate‐limiting enzyme catabolizing cholesterol to bile acids) in mice by repressing the murine small heterodimer partner (Shp), a negative repressor of Cyp7a1 (Goodwin et al, 2000).…”