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

H.P. Quach, Keumhan Noh, Stacie Y. Hoi, Adriaan Bruinsma, Genoveva Groothuis, Albert P. Li, Edwin C.Y. Chow, K. Sandy Pang

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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 D3 [1,25(OH)2D3], 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)2D3/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)2D3 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.
Original languageEnglish
Pages (from-to)99-115
Number of pages17
JournalBiopharmaceutics & drug disposition
Volume39
Issue number2
Early online date30-Jan-2017
DOIs
Publication statusPublished - Feb-2018

Keywords

  • DIETARY CALCIUM
  • MOUSE KIDNEY
  • PROTEIN-KINASE-C
  • MESSENGER-RNA EXPRESSION
  • FARNESOID-X-RECEPTOR
  • D RESPONSE ELEMENTS
  • 1-ALPHA,25-DIHYDROXYVITAMIN D-3
  • TISSUE DISTRIBUTION
  • IN-VIVO
  • PARATHYROID-HORMONE

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