VITAMIN D ENDOCRINE SYSTEMFROM EVOLUTION TO REVOLUTION

ByAHMED MOSTAFA TAHA MOHAMED

Borham_ahmad@yahoo.com

WHY EVOLUTION OF VIT D IS IMPORTANT?

Vitamin D as a unique ancient molecule and its related system , exposed to a lot of modifications through its journey in Biological history.

Also this functional and structural evolution helped us to understand the complexity of vit D system , up to considering it , An Endocrine System , Not just a simple Vitamin!!

It attracted to researchers all over world to uncover more and more of its mystery which reached new places that never crossed our imagination to be Vit D related !

I hope You will find this scientific Time journey with this Endocrine System is very interesting as giving you a new look to this important topic.Special Thanks to Prof. Sandro Mazzaferro and Prof.Marzia Pasquali who inspired me this presentation

Unstable Molecule

750 MILLION YEARS AGO

We can find the precursor of vitamin D3, 7-deydrocholesterol or pro-vitamin D3, in very old living organisms, such as plankton .

The synthetic pathway of this precursor is much conserved, starting from cholesterol. Just 2 hydrogen atoms removed. This resemblance allows us to hypothesize that in unicellular organisms, vitamin D3 was a component of the plasma membrane just like Cholesterol and synthesized from it. However ,a specific feature characterizes this pro-vitamin D3: the capacity of absorbing UV-B rays in the same wavelength of DNA. For this reason, the biological role of pro-vitamin D3 in ancient organisms could have been that of protecting DNA from the toxic effects of UV-B rays, rather than regulating Ca metabolism

Holick MF. Vitamin D: evolutionary, physiological and health perspectives.Curr Drug Targets 2011

PLANKTON

After UV-B ray absorption, pro-vitamin D3 is transformed into the thermodynamically unstable pre-vitamin D3, which requires a final transformation into the more stable cholecalciferol or vitamin D3 .As such, this new molecule could be regarded as an inactivated end-product.

However, in very old organisms like algae, it is capable of promoting growth activity,which points to the persistence of some biological effect.

Algae under microscope

ALgae

the specific enzymes capable of producing hydroxylated metabolites appear early in evolution, in yeasts and old plants that have no calcified structure .

A role for vitamin D in the process of mineralization can be seen some 550 MYA in snails and crustaceans, in which 25-hydroxyvitamin D (25OHD3) and 1,25-dihydroxyvitamin D

could have some implication in the mineralization processes

550 MILLION YEARS AGO

Marine Snails

450 MILLION YEARS AGO

jawless fishes that possess a type of vitamin D receptor (VDR), the complexity of the vitamin D system increases slightly. In these cartilaginous (non-calcified) fishes, however, this ancestral receptor is involved in xenobiotic detoxification which is considered as a type of immune response and not with calcification

Agnatha

Whitfield GK, Dang HT, Schluter SF et al. Cloning of a functional vitamin D receptor from the lamprey (Petromyzon marinus), an ancient vertebrate lacking a calcified skeleton and teeth. Endocrinology 2003

375 MLLION YEAR AGO

It is in teleosts (complete bone fishes) with cellular and remodelling bone that VDR activation, for the first time, is involved with calcium and phosphate absorption and bone mineralization

200-300 MILLION YEARS AGO

It is subsequently in terrestrial animals that the VDR becomes functionally divergent from that of aquatic animals by acquiring more definite ‘calcium-phosphate-oriented’ effectsAlong with the VDR, in vertebrates a specific vitamin D binding protein (DBP) also appears seemingly functional to the need of systemic transportation of the hydrophobic vitamin.This protein has a specific ligand binding domain (LBD) for vitamin D metabolites and circulates in excess amounts compared with ligands, thus representing a storage compartment. Further, it has different affinity for each of the vitamin D metabolites [e.g. 600 times higher for 25OHD3 than for 1,25(OH)2D3] and in this way regulates circulating levels of the free fractions of each metabolite

Howarth D, Law SHW, Barnes B et al. Paralogous vitamin D receptors inteleosts: transition of nuclear receptor function. Endocrinology 2008

WHY EARLY LIFE LACKED BONE?

We can notice this easily as life continued about 300 Million years without bone , and it started only when evolution is directed more toward the land surface.

The fact is plenty of calcium has been available in seawater (some 40 mg/dL) which is 4 times what present in human circulation as example showing no need for storing Ca in Bone , and lack of any need to Vit D calcium enhancing absorption , this metabolic view of our Bones can give us a new view.

Accordingly, defensive or detoxifying roles are the most probable functions of vitamin D in more simple life species in the sea.

FGF23/KLOTHO SYSTEM

FGF23 is the most famous phosphatonin , which is a group of proteins secreted to control phosphorus level through its phosphaturic effect with help of Klotho , also it downregulate Vit D which has a stimulatory effect on FGF gene , so there is regulatory effect between the two linked systems.

The complete biological relevance of the FGF23/Klotho system is still not settled and could possibly go beyond mineral metabolism, since direct cardiac effects have been demonstrated for both FGF23 and Klotho.Further, by regulating renal tubular Na-Cl cotransporters, FGF23 may influence blood volume and pressure , it started in bone vertebrates .

OSTEOCALCIN

OC has been considered a bone protein involved with mineralization processes. However, OC null mice show increased bone mass without mineralization defects in front of a clear phenotype of diabetes-obesity.we now know that a metabolite of OC, undercarboxylated OC, which is mainly produced during bone resorption, stimulates insulin secretion by the pancreatic β-cells and promotes insulin sensitivity in peripheral organs while also modulating adipocyte activity.

Importantly, by stimulating its own receptor on osteoblasts, insulin inhibits the synthesis of osteoprotegerin in these cells, thus increasing osteoclast recruitment, bone resorption and further OC production (Positive feedback). Vitamin D, which regulates bone cells in general and can either stimulate transcription or reduce circulating levels of OC , is thus involved with energy metabolism

VITAMIN D AND MUSCULOSKELETAL SYSTEM

Migration of life from sea to land carried some challenges like more need for calcium and minerals regulation in more tight way with storage urgency , and Bone solved this with help of Vit DSecond challenge was the need for more free movements and that happened with cooperation of the musculoskeletal system which is high energy consuming organ , as we can see the role of Vit D in regulation of such energy metabolism with mineral availability needed for Muscle contraction physiology.

VITAMIN D PLEIOTROPIC EFFECTS

From all what we studied through our Time journey with Vit D evolution , we can now have Idea , why Vitamin D only was the topic of more than 4000 paper in 2014 only , and why scientist was directed to new aspects of research which is slightly far from simple mineralization process to more wide systemic effects of Vitamin D endocrine system.

Vit D role in aspects like , immune modulation , cell proliferation and growth with its relation to cancer,apoptotic and antifibrotic studies , cardiovascular system and its role in Mortality , energy metabolism and DM, renoprotective

roles ….. Etc are almost inspired form the thorough study of Vit D Evolution .

VITAMIN D RENAL PROTECTIONSeveral studies have shown that the administration of vitamin D analogues attenuates

the renal damage in various experimental models of uraemia. nephrectomized rats treated with 1,25-(OH)2D3 and found that vitamin D reduces renal cell proliferation and glomerular growth as well as glomerulosclerosis and albuminuriaas indicators of progressive glomerular damage. With a similar subtotally nephrectomized rat model .

Vit D and its analogs can suppress macrophage infiltration, monocyte chemoattractant protein-1 (MCP-1) production, transforming growth factor-beta-1 (TGF-β1) mRNA and protein expression, and phosphorylation of Smad2, and these effects are amplified when blood pressure is controlled via renin–angiotensin system blockade.

The use of vitamin D analogues in chronic kidney diseases: possible mechanisms beyond bone and mineral metabolism NDT Plus (2009) 2: 205–212

CONTINUED

It is found that treatment with 1,25-(OH)2D3 abrogated podocytes injury, detected as desmin expression, and loss of nephrin and zonula occludens-1 (two slit diaphragm associated proteins) and glomerular polyanion staining, suggesting that vitamin D may revert proteinuria by counteracting glomerular podocyte injury. On the other hand, in a study of experimental obstructive nephropathy, a model that is characterized by predominant tubulointerstitial lesions, Tan et al. showed that paricalcitol significantly attenuated renal interstitial fibrosis, as demonstrated by a reduced interstitial volume, decreased collagen deposition and repressed mRNA expression of fibronectin and type I and type III collagens. Paricalcitol also preserved E-cadherin and reduced alpha-smooth muscle actin expression in vivo.In addition, paricalcitol suppressed renal TGF-β1 and its type I receptor expression

MORTALITY IN CKD AND DIALYSIS PATIENTS

The use of vitamin D analogues in chronic kidney diseases: possible mechanisms beyond bone and mineral metabolism NDT Plus (2009) 2: 205–212

DIABETIC NEPHROPATHY

Diabetic nephropathy needs special considerations because it is the leading cause of dialysis-dependent end-stage renal disease, and the renin– angiotensin system (RAS) is a major mediator of progressive renal injury in diabetic nephropathy. As discussed above, vitamin D negatively regulates the RAS, and the renal protective role of vitamin D in diabetic nephropathy has been specifically studied . Diabetic VDR knockout mice developed more severe albuminuria and glomerulosclerosis due to increased glomerular basement membrane thickening and podocyte effacement . More fibronectin and less nephrin were expressed in the VDR knockout mice compared to diabetic wild-type mice. In receptor knockout mice, increased renin, angiotensinogen, TGF-β and connective tissue growth factor accompanied the more severe renal injury.

RAAS BLOCK

Combined treatment with an ARB and a vitamin D analogue markedly ameliorated renal injury in the streptozotocin induced diabetes model due to the blockade of the compensatory renin rise by the vitamin D analogue, leading to more effective inhibition of the renin–angiotensin system . The combined treatment suppressed the induction of fibronection, TGF-β and MCP-1 and reversed the decline of slit diaphragm proteins nephrin, zonula occludens-1 and alpha-actinin-4. These were accompanied by blockade of intrarenal renin and angiotensin

BLOOD PRESSUREIn the last two decades, epidemiological studies have revealed an inverse relationship between the plasma 1,25-(OH)2D3 concentration and the blood pressure or the plasma renin activity in both normotensive men and patients with essential hypertension.Furthermore, it has been reported that vitamin D3 supplementation reduces blood pressure in patients with essential hypertension , and 1,25-(OH)2D3 treatment reduces blood pressure, plasma renin activity and Ang II levels in hyperparathyroidism patients.The effect of a vitamin D analogue on the renin– angiotensin system, however, may not be directed on renin alone.

showed that paricalcitol decreases angiotensinogen, renin, renin receptor and vascular endothelial growth factor mRNA levels in the remnant kidney by 30–50% as compared to untreated animals. Similarly, the protein expression of renin, renin receptor, the angiotensin type 1 receptor and vascular endothelial growth factor were all significantly decreased.

MYOCARDIUM EFFECTSVitamin D has a direct effect on myocardium, independent of its suppressive effect on the renin–angiotensin system. It directly suppresses myocardial hypertrophy and could improve cardiac performance.The uptake of calcium by cardiac muscle cells is in part regulated by vitamin D.O’Connell et al. showed that 1,25-(OH)2D3 reduces proliferation rate, PCNA levels and c-Myc levels of myocytes in culture through decreased entry into the S phase. Vitamin D deficiency also results in a shift in the tissue distribution of V1 and V3 myosin chains, favouring the V1 isotype . Shifts in myosin isotypes have been shown to alter myocyte contractility . In addition, vitamin D has a biphasic action on vascular smooth muscle cell and prevents its proliferationActive vitamin D also suppresses the stimulatory effect of epidermal growth factor on vascular smooth muscle cell proliferation.At low dose, vitamin D may also stimulate the production of inhibitors of arterial calcification and have an anti-thrombotic effect . In contrast, active form of vitamin D applied in supraphysiological concentration is a mitogenic factor for aortal smooth muscle cell

METABOLIC EFFECTS

Vitamin D has also been reported to enhance insulin sensitivity and induce a favourable plasma lipid profile.Chiu et al. found an independent correlation between serum 25(OH)D concentration and insulin sensitivity index, and an independent negative relationship of 25(OH)D concentration with plasma glucose concentration at fasting, 60, 90 and 120 min during the oral glucose tolerance test. In this study, subjects with hypovitaminosis D (below 20 ng/mL) had a greater prevalence of components of metabolic syndrome than did subjects without hypovitaminosis D. Vitamin D has also been reported to increase apolipoprotein A-I and high-density lipoprotein (HDL) cholesterol, resulting in a favourable plasma lipid profile

IMMUNOMODULATING EFFECTS

A vitamin D analogue is also a potent regulator of the immune system, in particular, on T cell-mediated immunity . Vitamin D receptor is found in significant concentrations in the T lymphocyte and macrophage populations However, its highest concentration is in the immature immune cells of the thymus and the mature CD8 T lymphocytes The significant role of vitamin D compounds as selective immunosuppressants is illustrated by their ability to either prevent or markedly suppress animal models of autoimmune disease. Results show that 1,25-(OH)2D3 can either prevent or markedly suppress experimental autoimmune encephalomyelitis, rheumatoid arthritis, systemic lupus erythematosus, type I diabetes and inflammatory bowel disease . Vitamin D hormone stimulates interleukin 4 (IL-4) production, which in turn suppresses inflammatory T cell activity . Calcitriol attenuates the expression of experimental murine lupus . In the kidney , 1,25(OH)2D3 also regulates mesangial cell smooth muscle phenotypes in a TGF-β1-mediated manner and ameliorates glomerular injury in rats with experimental glomerulonephritis

Vitamin D: a pleiotropic hormone Kidney international Vol 78, issue 2, 2 July 2010

CANCER

Several large-scale epidemiological studies have shown an inverse correlation between exposure to sunlight (the major source of vitamin D) or vitamin D intake and risk of colorectal, breast, and prostate cancer.Worldwide research has focused on the development of structural analogs of 1,25(OH)2D3 with a clear dissociation between antiproliferative and calcemic effects. One of these analogs, TX 522 (Inecalcitol;) is currently in phase II in patients with hormone-refractory prostate cancer. Preliminary results showed that 27 of the 31 patients treated with Inecalcitol (at different doses up to 600 mg per day) and Taxotere during 18 weeks showed a decrease in prostate-specific antigen levels of more than 30% within 3 months of initiation of treatment without any changes in calcium parameters

A recent meta-analysis of the association between serum 25(OH)D3 and colorectal cancer risk supports the conclusion that lower serum 25(OH)D3 levels are inversely associated with colorectal cancer.The association between breast cancer risk and 25(OH)D3 status has been studied among others in the United States as well as in Europe. The UK study showed that women with 25(OH)D3 levels o50nmol/l have an odds ratio of 3.54 for breast cancer risk compared with women with levels 450 nmol/l.From these studies, it became clear that not one single gene or one single pathway mediates the antiproliferative effects of 1,25(OH)2D3 but that multiple pathways are involved, among which epidermal growth factor,insulin-like growth factor, transforming growth factor, and prostaglandins signaling cascades.

BONE AND CALCIUM HOMEOSTASIS1a,25-Dihydroxyvitamin D3 (1,25(OH)2D3) is a major calcitropic hormone with as primary purpose to keep the plasma Ca concentration within narrow limits. The renal production of 1,25(OH)2D3 is therefore tightly regulated by two hormones. First, hypocalcemia induces the secretion of parathyroid hormone (PTH) by the parathyroid gland PTH targets the kidney to decrease Ca excretion, inhibit phosphate reabsorption, and stimulate 1,25(OH)2D3 production. 1,25(OH)2D3 will then increase active Ca and phosphate transport in the small intestine and stimulate Ca reabsorption in the kidney. In concert with the effects of PTH on bone, 1,25(OH)2D3 action also enhances Ca exchange from bone and the cooperation of these pathways restores serum Ca levels to normal. Second, 1,25(OH)2D3 stimulates the secretion of FGF23 by the osteocytes. FGF23 is the major phosphaturic hormone inhibiting renal phosphate reabsorption (by the specific transporter NaPiT2a) and decreasing the renal production of 1,25(OH)2D3. In addition, 1,25(OH)2D3 and phosphate stimulate and FGF23 inhibits PTH production creating a true phosphate feedback loop.

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