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. 2013 Jan 10;5(1):111–148. doi: 10.3390/nu5010111

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© 2013 by the authors; licensee MDPI, Basel, Switzerland.

This article is an open-access article distributed under the terms and conditions of the Creative Commons Attribution license (http://creativecommons.org/licenses/by/3.0/).

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Metabolism of 25-hydroxyvitamin D [25(OH)D] to 1,25 dihydroxyvitamin D 1,25(OH)₂D for non-skeletal functions. When a monocyte/macrophage is stimulated through its toll-like receptor 2/1 (TLR2/1) by an infective agent such as Mycobacterium tuberculosis (TB), or its lipopolysaccharide (LPS) the signal upregulates the expression of vitamin D receptor (VDR) and the 25-hydroxyvitamin D-1-hydroxylase (1-OHase). 25(OH)D levels >30 ng/mL provides adequate substrate for the 1-OHase to convert it to 1,25(OH)₂D. 1,25(OH)₂D returns to the nucleus where it increases the expression of cathelicidin which is a peptide capable of promoting innate immunity and inducing the destruction of infective agents such as TB. It is also likely that the 1,25(OH)₂D produced in the monocytes/macrophage is released to act locally on activated T (AT) and activated B (AB) lymphocytes which regulate cytokine and immunoglobulin synthesis respectively [143,144,145,146,147]. When 25(OH)D levels are ~30 ng/mL, it reduces risk of many common cancers [130,131,132,133,134,135,136,137,138,139,140]. It is believed that the local production of 1,25(OH)₂D in the breast, colon, prostate, and other cells regulates a variety of genes that control proliferation. Once 1,25(OH)₂D completes the task of maintaining normal cellular proliferation and differentiation, it induces the 25-hydroxyvitamin D-24-hydroxylase (24-OHase). The 24-OHase enhances the metabolism of 1,25(OH)₂D to calcitroic acid which is biologically inert [7,18]. Thus, the local production of 1,25(OH)₂D does not enter the circulation and has no influence on calcium metabolism. The parathyroid glands have 1-OHase activity [45] and the local production of 1,25(OH)₂D inhibits the expression and synthesis of PTH [74]. The production of 1,25(OH)₂D in the kidney enters the circulation and is able to downregulate renin production in the kidney [148,149] and to stimulate insulin secretion in the β-islet cells of the pancreas [148,150]. Note: This figure is reproduced with permission from [21], Copyright © 2007 Michael F. Holick.