Vitamin D absorption, transport and metabolism Domina Petric, MD

Enteric absorption of vitamin D 11/19/2018 Combs GF. The Vitamins. Fundamental Aspects in Nutrition and Health. Elsevier Inc. 2008.

Enteric absorption of vitamin D Vitamin D is absorbed from the small intestine by nonsaturable passive diffusion that is dependent on micellar solubilization and the presence of bile salts. The fastest absorption appears to be in the upper portions of the small intestine: the duodenum and jejunum. Owing to the longer transit time of food in the distal portion of the small intestine, the greatest amount of vitamin D absorption probably occurs in ileum. 11/19/2018 Combs GF. The Vitamins. Fundamental Aspects in Nutrition and Health. Elsevier Inc. 2008.

Enteric absorption of vitamin D Vitamin D enters the lymphatic circulation predominantly (about 90% of the total amount absorbed) in association with chylomicra, with most of the balance being associated with the α-globulin fraction. The efficiency of this absorption process for vitamin D appears to be about 50%. 11/19/2018 Combs GF. The Vitamins. Fundamental Aspects in Nutrition and Health. Elsevier Inc. 2008.

Transport of vitamin D II. 11/19/2018 Combs GF. The Vitamins. Fundamental Aspects in Nutrition and Health. Elsevier Inc. 2008.

Transfer from chylomicra to a plasma Almost all absorbed vitamin D is retained in non esterified form, which is associated with the surface of chylomicrons (lipoprotein particles). A portion of the vitamin D can be transferred from chylomicra to a binding protein in the plasma, either directly or during the process of chylomicron degradation. Vitamin D that is not transferred in the plasma is taken up with chylomicron remnants by the liver, where it is transferred to the same binding protein and released to the plasma. 11/19/2018 Combs GF. The Vitamins. Fundamental Aspects in Nutrition and Health. Elsevier Inc. 2008.

Vitamin D binding protein Vitamin D-binding protein (DBP) is a glycosylated, cysteine rich, α-globulin of 55 kDa and 458 amino acids. It binds vitamins D2 or D3 and their metabolites stoichiometrically, with ligand-binding dependent on the cis-triene structure and C3-hydroxyl grouping. 11/19/2018 Combs GF. The Vitamins. Fundamental Aspects in Nutrition and Health. Elsevier Inc. 2008.

Vitamin D binding protein DBP is depressed in patients with hepatic disease. It is increased during estrogen therapy or pregnancy. It does not appear to cross the placenta. 11/19/2018 Combs GF. The Vitamins. Fundamental Aspects in Nutrition and Health. Elsevier Inc. 2008.

Vitamin D binding protein DBP mobilizes the vitamin produced endogenously in the skin. The efficiency of endogenously produced vitamin D3 is greater than that given orally: the former enters the circulation strictly via DBP, whereas orally given enters as complexes of DBP as well as chylomicra. DBP protein has also been found on the surfaces of lymphocytes and macrophages. 11/19/2018 Combs GF. The Vitamins. Fundamental Aspects in Nutrition and Health. Elsevier Inc. 2008.

Tissue distribution Vitamin D is not stored by the liver. It reaches the liver within a few hours after being absorbed across the gut or synthesized in the skin. From the liver it is distributed relatively evenly among the various tissues, where it resides in hydrophobic compartments. Fatty tissues such as adipose show slightly greater concentrations. 11/19/2018 Combs GF. The Vitamins. Fundamental Aspects in Nutrition and Health. Elsevier Inc. 2008.

Tissue distribution About half of the total vitamin D in the tissues occurs as the parent vitamin D3 species, with the next most abundant form, 25-OH-D3 (20%). In the plasma, 25-OH-D3 predominates by several fold. Tissues including those of the kidneys, liver, lungs, aorta and heart also tend to accumulate 25-OH-D3. 11/19/2018 Combs GF. The Vitamins. Fundamental Aspects in Nutrition and Health. Elsevier Inc. 2008.

Vitamin D receptors Vitamin D receptors (VDRs) have been identified in more than 30 different cell types. These include cells closely related to the maintenance of calcium homeostasis as well as immune, endocrine, hematopoetic, skin and tumor cells. 11/19/2018 Combs GF. The Vitamins. Fundamental Aspects in Nutrition and Health. Elsevier Inc. 2008.

Vitamin D receptors Organ system Cell type Bone Osteoblasts Alimentary tract Epithelial cells, enterocytes, colonocytes, stomach Liver Hepatocytes Kidney Epithelial (proximal and distal) cells Heart Atrial myoendrocrine cells, heart muscle cells Skeletal, smooth muscle Myocytes Cartilage Chondrocytes 11/19/2018 Combs GF. The Vitamins. Fundamental Aspects in Nutrition and Health. Elsevier Inc. 2008.

Vitamin D receptors Organ system Cell type Hematolymphopoetic Activated T and B cells, macrophages, monocytes, spleen, thymus reticular cells and lymphocytes, lymph nodes, tonsillary dendritic cells Reproductive Amnion, chorioallantoic membrane, epididymus, mammary gland alveolar and ductal cells, ovary, oviduct, placenta, testis Sertoli and Leydig cells, uterus, yolk sac Skin Epidermis, fibroblasts, hair follicles, keratinocytes, melanocytes, sebaceous glands Nervous Brain (hippocampus, cerebellar Purkinje and granule cells, bed nucleus, stria terminalis, amygdala central nucleus), sensory ganglia, spinal cord Other endocrine Adrenal medulla and cortex, pancreatic b cells, pituitary, thyroid follicles and C cells, parathyroid gland Other Bladder, choroid plexus, lung, endothelial cells, parotid gland 11/19/2018 Combs GF. The Vitamins. Fundamental Aspects in Nutrition and Health. Elsevier Inc. 2008.

Metabolism of vitamin D III. 11/19/2018 Combs GF. The Vitamins. Fundamental Aspects in Nutrition and Health. Elsevier Inc. 2008.

Metabolic activation of vitamin D 25-hydroxylation 1-hydroxylation 11/19/2018 Combs GF. The Vitamins. Fundamental Aspects in Nutrition and Health. Elsevier Inc. 2008.

25-hydroxylation Most of the vitamin D taken up by the liver from either DBP or lipoproteins is converted by hydroxylation of side-chain carbon C-25 to yield 25-OH-D3 (calcidiol). Enzyme is vitamin D 25-hydroxylase. Calcidiol is the major circulating form of the vitamin. 25-hydroxyvitamin D3 is not retained within the cell, but is released to the plasma where it accumulates by binding with DBP. 11/19/2018 Combs GF. The Vitamins. Fundamental Aspects in Nutrition and Health. Elsevier Inc. 2008.

25-hydroxylation The circulating level of 25-OH-D3, normally 10–40 ng/ml (25–125 nM), is a good indicator of vitamin D status. 11/19/2018 Combs GF. The Vitamins. Fundamental Aspects in Nutrition and Health. Elsevier Inc. 2008.

1-hydroxylation The initial hydroxylation product of vitamin D (25-OH-D3) is further hydroxylated at the C-1 position of the A ring to yield 1,25-(OH)2-D3. This hydroxylation is catalyzed by 25-OH-vitamin D 1-hydroxylase. This activity is located primarily in renal cortical mitochondria, but also in mitchondrial and microsmal fractions of at least some extrarenal tissues: bone cells, liver, placenta. 11/19/2018 Combs GF. The Vitamins. Fundamental Aspects in Nutrition and Health. Elsevier Inc. 2008.

1-hydroxylation The 1-hydroxylase uses NADPH2 as the electron donor and has three constituent proteins: ferridoxin reductase ferridoxin cytochrome P-450 11/19/2018 Combs GF. The Vitamins. Fundamental Aspects in Nutrition and Health. Elsevier Inc. 2008.

Catabolism of vitamin D 24-Hydroxylation 11/19/2018 Combs GF. The Vitamins. Fundamental Aspects in Nutrition and Health. Elsevier Inc. 2008.

24-hydroxylation Hydroxylation at the C-24 of the side chain can occur to both 25-OH-D3 or 1,25-(OH)2-D3 to produce the di- and tri-hydroxy metabolites 24,25-(OH)2-D3 (calcidiol) and 1,24,25-(OH)3-D3 (calcitroic acid or calcitriol). The 24-hydroxylase has a 10-fold greater affinity for 1,25-(OH)2-D3 than for 25-OH-D3. The greatest activity of the 24-hydroxylase is found in renal mitochondria. 11/19/2018 Combs GF. The Vitamins. Fundamental Aspects in Nutrition and Health. Elsevier Inc. 2008.

24-hydroxylation 24-hydroxylase is a cytochrome P-450- dependent enzyme requiring NADPH. It is inhibited by hypercalcemia and hyperphosphatemia. Both calcitriol and 24,25-(OH)2-D3 appear to be produced under conditions of vitamin D adequacy and normal calcium homeostasis. Calcitriol is a major biliary metabolite of the vitamin. 11/19/2018 Combs GF. The Vitamins. Fundamental Aspects in Nutrition and Health. Elsevier Inc. 2008.

Regulation of vitamin D metabolism IV. 11/19/2018 Combs GF. The Vitamins. Fundamental Aspects in Nutrition and Health. Elsevier Inc. 2008.

Regulation of vitamin D metabolism The dominant renal synthesis of 1,25-(OH)2-D3 is effected by the responses of parathyroiod hormone (PTH) and calcitonin (CT) to serum levels of Ca2+ and phosphate. 11/19/2018 Combs GF. The Vitamins. Fundamental Aspects in Nutrition and Health. Elsevier Inc. 2008.

Renal synthesis of 1,25-(OH)2-D3 is increased when: Serum Ca2+ is low, the Ca receptor mediated stimulation of the parathyroid to produce PTH, stimulates an increase in the renal 1-hydroxylase activity. 11/19/2018 Combs GF. The Vitamins. Fundamental Aspects in Nutrition and Health. Elsevier Inc. 2008.

Renal synthesis of 1,25-(OH)2-D3 is increased when: Serum phosphate is low (in the presence of normal serum Ca2+), an unknown mechanism that appears to involve a pituitary gland hormone increases the 1-hydroxylase. 11/19/2018 Combs GF. The Vitamins. Fundamental Aspects in Nutrition and Health. Elsevier Inc. 2008.

Renal synthesis of 1,25-(OH)2-D3 is increased when: Serum levels of both Ca2+ and phosphate are low, both mechanisms result in the superstimulation of the 1-hydroxylase. 11/19/2018 Combs GF. The Vitamins. Fundamental Aspects in Nutrition and Health. Elsevier Inc. 2008.

Renal 1-hydroxylase The hormones PTH and CT both stimulate the renal 1-hydroxylase. The effect of PTH is rapid and mediated by cAMP. The effect of CT is relatively slow, apparently acting at the level of transcription. 11/19/2018 Combs GF. The Vitamins. Fundamental Aspects in Nutrition and Health. Elsevier Inc. 2008.

Production of D3 in macrophages In macrophages, the production of 1,25-(OH)2-D3 has been found to be insensitive to PTH but to be stimulated by such immune stimuli as interferon-gamma and lipopolysaccharide. 11/19/2018 Combs GF. The Vitamins. Fundamental Aspects in Nutrition and Health. Elsevier Inc. 2008.

Catabolism The catabolism of 1,25-(OH)2-D3 is regulated by PTH, serum phosphate, and factors affecting the principal catabolizing enzyme, the hepatic 24-hydroxylase. When circulating levels of 1,25-(OH)2-D3 are high, its renal synthesis is low. The tight regulation of the 1-hydroxylase activity results in the maintenance of nearly constant plasma concentrations of 1,25-(OH)2-D3. 11/19/2018 Combs GF. The Vitamins. Fundamental Aspects in Nutrition and Health. Elsevier Inc. 2008.

1,25-(OH)2-D3 1,25-dihydroxyvitamin D3 activates its own breakdown by stimulating the transcription of the 24-hydroxylase gene. This stimulation is suppressed in conditions of low serum phosphate. 11/19/2018 Combs GF. The Vitamins. Fundamental Aspects in Nutrition and Health. Elsevier Inc. 2008.

Literature Combs GF. The Vitamins. Fundamental Aspects in Nutrition and Health. Elsevier Inc. 2008. 11/19/2018 Combs GF. The Vitamins. Fundamental Aspects in Nutrition and Health. Elsevier Inc. 2008.