HUN 4221 Vitamin D

Renal 1-hydroxylase Activity stimulated by:

- low concentration of 1, 25-(OH)2 D3 (feedback inhib.) - low plasma calcium - low phosphorous intake - parathyroid hormone (PTH): most potent inducer; stimulates transcription of 1-hydroxylase gene

Vitamin D: Hepatic metabolism

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Steps of 1,25-(OH)2 D3 and Ca2+ absorption

1. VDR complex enters nucleus 2. VDR complex forms heterodimer with RXR 3. Binds VDRE 4. Change in gene expression 5. Upregulation of calbindin enhances Ca2+ absorption

24, 25-OH Cholecalciferol

24-hydroxylase in kidney mades from 25-Oh Cholecalciferol, released into blood goes to various tissues, an indicator that there's enough VIt D and whats there is being prepared for excretion (high calcitriol)

Vitamin D Absorption Reduction

Absorption can be reduced in clinical conditions that reduce fat absorption: e.g., cystic fibrosis, celiac disease, Chron's disease, bypass surgery, medications that reduce cholesterol absorption

Vitamin D Hx: 1928 Nobel Prize in Chemistry

Adolf Windaus warded "for the services rendered through his research into the constitution of the sterols and their connection with the vitamins "

Vitamin D: Upper Level (UL)

Adults 4000

Vitamin D: Recommended Intakes

Adults: 600 IU

Vitamin D: Food Sources

Almost exclusively in animal foods: Sardines Poultry Skin Herring Liver Oil

High Prevalence of Vitamin D Insufficiency in Black and White Pregnant Women Residing in the N U.S> and their Infants

Black women majority deficient or insufficient (infants the same) Amts lowest in Spring b/c stores depleted over winter

1,25(OH)2 D3 and Ca2+ Absorption Mechanism

Calcitriol (produced in the kidney) travels to intestine and will bind bit D receptor on enterocyte surface travels to nucleus cause gene transcription of calbindin, Apical and Basolateral Absorption poorly understood, we know Calbindin plays a roll

Plasma transport of 1,25-(OH)2 D3

DBP loosely binds 1, 25-(OH)2 D3 to facilitate its release to tissues

Age and skin synthesis of D3

Elderly have difficulty making bit D from the sun resulting in a higher dietary requirement

How is VIt D helping in Ca2+ absorption?

Enhances transcription of calbindin which enhances absorption of Ca2+

Vitamin D: 37th Parallel

Except during the summer months the skin makes little if any vit D at latitudes above 37 degrees north (in the US, shaded) or below 37 degrees south of the equator. People in these areas at greater risk for vit D deficiency.

Vitamin D

Fat soluble vitamin

What do Vit D and Vit A have in common?

Fat soluble, mechanism of absorption, both potent inducers of gene expression

25-OH Cholecalciferol

Formed from VIt D3, status indicator in liver

1, 25-OH Cholecalciferol

In kidney, Active form made from 25-OH califerol by 1-hydroxylase (low Ca, high PTH, -P)

Fat soluble Vitamin Absorption Similarities

Intestinal absorption: Micelle-> chylomicron-> lymph system

Transcellular Ca2+ reabsorption

Kidney reabsorbes Ca@+ by protein TRFVS located on the cell's glomerulus, pumps Ca2+ in and it can renter blood

Vitamin D Clinical Trials

Large clinical trials with lots of pts

Knockout Mice Experiment: deleting 1-Hydroxylase Enzyme

Made 1,25(OH)D3 concentration lower until bend ND at 3 weeks, 25(OH)D3 inc, PTH inc, serum Ca lvls dec

Resorption of Ca2+ by kidney

Reabsorption: movement of substances out of renal tubule back into the blood Blood passes glomerulus, filtering Ca out of proximal tubule using PTH

Rickets in the US

Recent reports of rickets in the US Particular problem in African- American breast-fed infants -Skin pigmentation reduces UV exposure -Lactose intolerance may decrease consumption of vitamin D-fortified milk

Vitamin D Hx: London 1634

Rickets surfaces as a cause of death on the general bill of health (death tally) kills 14

Vitamin D: Chemistry- Isoprenoid Units

Squalene derivative makes 7-dehydrocholestrol which reacts with UV light by two steps in the skin to form vitamin D3 (Make vitamin D in skin from cholesterol)

Vitamin D synthesis in skin

Sun converts 7-dehydrocholesterol into vitamin D3, vitamin D can enter blood stream where it binds Vit D Binding Protein

25(OH) VItD Assay

Tells you Vit D status, 1,25(OH)D3 is elevated in deficient state

Vitamin D Hx: 1936

Two forms of vitamin D are described: D2 and D3

1,25-(OH)2 D3 and gene expression

VDR binds VD-> heterodimer w/ RXR-> binds VDRE-> change in gene expression= protein synthesis

Which Vitamins have isoprenoid units in their structure?

Vit A, K, D

1,25-(OH)2 D3 and RANKL expression

Vit D binds VDR-> heterodimer w/ RXR-> binds to DNA-> effects gene expression (RANKL inc)

Transport of D3 from skin to liver

Vitamin D Binding protein is synthesized in the liver can carry vitamin D from diet or made in skin

VDRE

Vitamin D Response Element

24-hydroxylase in kidney

When this form of Vit D appears there is a high level of vitamin D (High calcitriol) broken down from this form (24,25-(OH)2 cholecalciferol in blood) and excreted

Vitamin D Hx: Huldschinsky 1920s

cures rickets with ultraviolet light lamp

Vitamin D Hx: Daniel Whistlet

first scientific investigation of the rickets, first description of the rickets

Vitamin D Hx: Mellanby 1919

nduces rickets in puppies by feeding a low- fat diet; could be treated with cod liver oil and butter; concludes that rickets is caused by vitamin A deficiency

Vitamin D Hx: Trousseau 1865

recommends cod liver oil as treatment for ricketsTrousseau

Artile: Game addict kids hit by extinct bone disease

sensational bit the bone disease much more common than we realize, has lead to inc in RDA to higher amt

Vitamin D Hx: McCollum 1922

shows that heating cod liver oil destroyed xeropthalmic (vitamin A) activity, but retained anti- rachitic activity; calls heat-stable factor "vitamin D"

Vitamin D Hx: Whistler 1645

writes first scientific description of rickets

1,25-(OH)2 D3: osteoclast maturation

• 1, 25-(OH)2 D3 and PTH induce the expression of receptor activator of NFkB ligand (RANKL) on osteoblast • RANKL interacts with receptor protein RANK on preosteoclast, causing it to mature into osteoclast

1,25-(OH)2 D3 and Ca2+ homeostasis

• 1, 25-(OH)2 D3 helps to maintain blood [Ca2+] by acting on: - intestine: increases Ca2+ absorption - kidney: increases Ca2+ reabsorption - bone: increases Ca2+ mobilization from bone • Works with parathyroid hormone, PTH, the major regulator of blood [Ca2+]

Renal 1-hydroxylase

• A cytochrome P450 monooxygenase (CYP27PB1)

Calcibindin

• Binds to Ca2+ and directs its across enterocyte (helps direct to basolateral membrane) • 1, 25-(OH)2 D3 increases transcription of calbindin • Calbindin expression decreases in vit D deficiency

1,25-(OH)2 D3 and bone resorption

• Bone resorption: process by which osteoclasts break downboneandreleaseCa2+ andP • 1, 25-(OH)2 D3 stimulates (through osteoblasts) the maturation of osteoclasts • Osteoclasts release HCl and hydrolytic enzymes that dissolve and catabolize bone matrix, releasing Ca2+ and P into the blood

Vitamin D: Skin pigment

• Dark-skinned individuals may required 5-10 X more sun exposure to generate same amount of D3 as light-skinned individuals

Nuclear Vitamin D Receptor (VDR)

• Found in bone, intestine, kidney, skin, etc. • VDR belongs to superfamily of nuclear receptors, including those for retinoic acid, thyroid, and steroid hormones • VDR binds to 1, 25-(OH)2 D3 and forms heterodimer with RXR • 1,25-(OH)2 D3 -VDR-RXR complex binds to VDRE and stimulates transcription of genes

Vitamin D-fortified foods

• In US and Canada, milk is routinely fortified with vitamin D as are some orange juices, cereals, yogurts, cheeses, infant formula • In Europe only a few countries fortify with vitamin D (Finland- cod liver oil)

Vitamin D: Deficiency

• Infants and children: rickets • Failure of bone to mineralize • Growth retardation • Long bongs of legs bow or knock • Adults: osteomalacia • Demineralization of bone, resulting from inadequate amounts of Ca and P

1,25-(OH)2 D3 Function in Skin Cells

• Keratinocytes in skin not only major source for 7- dehydrocholesterol which can be converted to D3 when exposed to sunlight but also - Keratinocytes have vitamin D receptors (VDR) and are a "target tissue" for 1,25 D3 - Interaction of 1,25 D3 and VDR activates the transcription of 1,25 D3 sensitive target genes involved in cell differentiation and proliferation - In vitro studies with keratinocytes incubated with 1,25 D3 revealed a marked decrease in DNA synthesis and proliferation

Vitamin D toxicity

• No risk of vitamin D toxicity from sun exposure • Toxicity from oral vitamin D very rare • 10,000 IU per day for several months results in hypercalcemia and calcification of soft tissues

Vitamin D: Food Forms: Cholecalciferol (Vitamin D3)

• Only found in animals • Fish liver and fish oils

Other tissues that respond to 1,25-(OH)2 D3

• Other target tissues and vitamin D deficiency outcomes: animal models and some human studies • Pancreas- increased diabetes risk • Brain-abnormal behavioral changes • Immune cells-autoimmune disease • Skin-abnormal cell differentiation

Vitamin D: Food Forms: Ergocalciferol (Vitamin D2)

• Plant form • Present in only small amounts • Common supplement form • Less biologically active than D3 (effectively the same)

1,25(OH)2 D3 and Ca2+ absorption

• Primary function of 1, 25-(OH)2 D3 is to increase the absorption of Ca2+ (and P) - Partially responsible for antirachitic action of 1, 25-(OH)2 D3

Clinical and Public Health Application of Vitamin D3 Supplements

• Psoriasis • Osteomalacia/osteoporosis prevention • Muscle strength- fall prevention • BoneIntegrity - fracture prevention older individuals - bone density of fetus and children • Cancer • Multiple Sclerosis

Factors affecting skin synthesis of D3

• Sun exposure: more exposure = more vitamin D • Latitude • Season • Time of day • Weather conditions • Sunscreen • Skin pigment:

Blood Ca2+ homeostasis

• Tightly regulated from 9-11 mg/100 mL • Ca2+ is required for: - Nerve and muscle cells - Blood clotting - Enzymes as a cofactor • Hypo/hyper-calcemia can result in death • Main purpose of 1, 25-(OH)2 D3 and PTH is to provide plasma Ca2+ for neuromuscular function

1,25-(OH)2 D3: Mechanisms of action

• Two main mechanisms of functioning: • Functions like a hormone - binds to membrane receptor on target tissues and activates a signal transduction pathway • Affects gene expression - binds to nuclear receptor and affects transcription

1,25-(OH)2 D3: Effect in Brain

• VDR present in brain - Function of 1,25(OH)2D3 in brain unknown • VDR knockout mouse model - One symptom is behavioral change • On-going research to understand link between vitamin D and behavior - Human and animal

1,25-(OH)2 D3 and Immune Function

• VDR present in hematopoietic cells involved in immune response • Induction of differentiation of precursor cells to monocytes and macrophages • Studies suggest role in "innate" immunity • Used clinically to treat autoimmune diseases

1,25-(OH)2 D3: Effect in Pancreas

• VDR present in pancreas • 1,25(OH)2D3 essential for normal insulin secretion • Vitamin D deficient patients have been shown to have impaired insulin secretion • Mouse model data suggest Vit D involvement in preventing Type I diabetes • Observational studies suggest that vitamin D supplements in infancy and childhood may decrease risk of Type I diabetes