VITAMIN D IN DEPTH OF BASICSAhmed Moustafa Taha Mohamed

DaVita KSA

Buraydah Center

WHAT IS VITAMIN D

a group of fat Soluble secosteroids responsible for enhancing intestinal absorption of calcium, iron,magnesium, phosphate, and zinc. In humans, the most important compounds in this group are vitamin D3 (also known as cholecalciferol) and vitamin D2 (ergocalciferol)

VITAMIN D RECENT MEDICAL HISTORY

Groundbreaking discoveries of the early 20th century elucidated vitamin D's essential role in calcium and phosphate homeostasis, bone mineralization and enabled major public health advances. The capacity of a novel fatsolublevitamin that was distinct from vitamins A, B or C, for prevention of experimental Rickets was shown in a seminal study by Mellanby. Subsequently, Chick et al. demonstrated that clinical Rickets could be cured by dietary cod liver oil supplementation or sunlight exposure . The Nobel prize in Chemistry was awarded to Dr Adolf Windaus in 1928, in recognition of his achievement in isolation of vitamin D and demonstration of its steroid structure . In the 1930s, fortification of milk with vitamin D virtually eradicated Rickets from the United States.

VIT D STRUCTURE

VIT D DYNAMIC MOLECULE

1α,25(OH) D , the most active form of vitamin D, is a highly flexible molecule with a steroid carbon skeleton with 4 rings A–D.

Unlike other steroids, in B ring , the 9–10 carbon bond is broken, thus creating a conformationally flexible molecule in which the “A” ring may rotate

This has a great value in synthesis of many Analogues of Vitamin D such as alpha calcidiol , paricalcitol , doxercalciferol …. etc , while we will not Finde such wide variability in synthetic analogs in other vitamains

VIT D DYNAMIC MOLECULE

What is Vit D2 , D3 ?

Is there Vit D1?

TYPES OF VITAMIN D

VITAMIN D METABOLISM

What is

Calcitriol Calcidiol 25 OH(vit D)1,25 OH (Vit D)

HOW VITAMIN D TRANSPORTED

As Vitamin D is Fat soluble , it cannot circulate such as in Blood , and needs what is called Binding Protein to be water soluble as a character of proteins , it called VIT D BP or DBP

Both calcidiol and calcitriol are carried on this DBP

Only tiny amount is Free , and this amount is the Biologically active portion ( usually not exceed 0.4%)

DBP functions to maintain stable serum stores of vitamin D metabolites, modulate bioavailability and influence responsiveness of some end organs

VITAMIN D RECEPTOR (VDR)

calcitriol receptor, also known as the vitamin D receptor (VDR) and also known as (nuclear receptor subfamily 1, group I, member 1), is a member of the nuclear receptor family of transcription factors. Upon activation by vitamin D, the VDR forms aheterodimer with the retinoid-X receptor RXR and binds to hormone response elements VDRE on DNA resulting in expression or transrepression of specific gene products.

This receptor is nonspecific for Vitamin D ,also it functions as a receptor for the secondary Bile acid lithocholic acid.Also almost all Vit D analog can be recognized by this cytoplasmic and

nuclear receptor

VITAMIN D HAS 2 MAIN METHODS OF ACTION

Slow GenomicRapid Non Genomic

1Α,25(OH) D /VDR MEDIATED GENOMIC RESPONSES

VDR induce4d gene transcription through hetero dimerization with one of the 3 (RXR) isoforms + a coregulatory protein, then this complex and binds to cognate vitamin D responsive elements (VDREs) in the promoter region of target genes.

1α,25(OH) D may regulate genes that do not contain VDREs within their promoter regions, through non genomic VDR actions

Regulation of gene expression by 1α,25(OH) D genomic signaling, is dependent upon the ability of VDR/RXR heterodimers to recruit coregulatory protein complexes

COREGULATORY MECHANISIMS

The ability of VDR/RXR heterodimers to recruit coregulatory protein complexes that may activate or repress target gene expression.

Ligand triggered conformational change of VDR–RXR heterodimers results in dissociation of corepressor proteins .

So different responses that we gain from the same substance (as Vitamin D) , with same receptor (VDR) in different tissues or cells can be attributed to , these cells specific co regulatory proteins which can change the end response ( targeted gene or produce new molecule as example) so new response will be gained !

That can explain what we know now about very wide Varity of actions done by VIT D !!

NEGATIVE REGULATORY EFFECTS

Example :

VDR may also repress gene transcription. CYP27B1 catalyzes the metabolic activation of 1α,25(OH) D from its precursor and is negatively regulated by 1α,25(OH) D , in a cell lineage specific and tissue restricted manner. CYP27B1 and other genes including PTH [30] are thought to be suppressed by 1α,25(OH) D via

negative vitamin D response elements (VDREs)

RAPID NON GENOMIC ACTIONS

This active sterol can also elicit rapid responses in target cells of the vitamin D endocrine system. Effects include

generation of calcium or ion flux .

induction of second messenger systems (G coupled receptors ).

activation of cytosolic kinases.

These effects occur rapidly within minutes and are considered incompatible with mechanisms involving alterations in gene transcription and protein synthesis .

Involvement of VDR in this pathway remains controversial, since rapid actions of 1α,25(OH) D may be invoked in cells that lack VDR.

DUAL REGULATION OF GENE EXPRESSION BY GENOMIC AND RAPID NON GENOMIC

PATHWAYSthe rapid non genomic activation of signal transduction pathways by 1α,25(OH) D can interact with and modulate VDR dependent gene transcription, So both pathways act in harmony . While the 1α,25(OH) D liganded RXR–VDR heterocomplex selectively recognizes VDREs in the promoter regions of osteopontin (OPN) and osteocalcin (OCN) genes as examples, the steady state levels of OPN and OCN mRNA can also be modulated by 1α,25(OH) D rapid non genomic actions !

antagonism of the nongenomic pathway blocks 1α,25(OH) D mediated

OCN expression . 1α,25(OH) D rapid activation of cytosolic kinases may

phosphorylate critical coactivators resulting in modulation of VDR dependent

gene transcription .

EXAMPLE

By non genomic actions, 1α,25(OH) D can modulate a repertoire of cytosolic kinases and second messenger systems that show some level of cell or tissues specificity e.g. activation of phospholipase A2 in chondrocytes and protein kinase A in enterocytes . By crosstalk with VDR/VDRE regulation of gene transcription, these membrane mediated kinase cascades may influence cells specific biological responses to 1α,25(OH) D , involved diverse physiological and pathobiological processes

TISSUE AND CELL SPECIFICITYOF VITAMIN D BIOLOGICAL EFFECTS

Most tissues express the receptor for 1α,25(OH) D (VDR) and renal tubules, skin, bone, brain, breast, colon and prostate also contain the enzyme CYP27B1, required for converting the major circulating metabolite of vitamin D,[25(OH)D] to 1α,25(OH) D . Notwithstanding the wide distribution of VDR and CYP27B1, 1α,25(OH)D shows highly tissue specific functional effects on hormone secretion, immune function, cell differentiation and growth. For example, 1α,25(OH) D inhibits PTH secretion in the parathyroid glands but stimulates pancreatic βcell insulin secretion.

VITAMIN D ENDOCRINE SYSTEM

From all this we can conclude that we are in front of a complete endocrine system not just a simple vitamin

1α,25(OH) D inhibits PTH secretion in the parathyroid glands but stimulates pancreatic βcell insulin secretion ,

inhibits adaptive immunity but enhances some innate immune responses inhibits differentiation of B lymphocytes but enhances keratinocyte differentiation

1α,25(OH) D mediated growth effects may show similar cell specificity.

For example

1α,25(OH) D has antiproliferative effects in some neoplastic cells but induces a spectrum of growth responses in others.

Adams JS and Hewison M (2008) Unexpected actions of vitamin D: new perspectives on the regulation of innate and adaptive immunity

Nat Clin Pract Endocrinol Metab

Vitamin D and innate immunity