Vitamin D
osteomalacia
-D deficiency in adults and is a defect in mineralization -The defect results from abnormal phosphorus and calcium absorption and excretion -For example, with Vit D deficiency, less calcium is absorbed -Declining blood calcium triggers secretion of PTH -If conditions persist, PTH remains elevated in the blood for prolonged periods and this can lead to bone resorption, and increased urinary phosphorus excretion, among other changes -In Vit D-deficient adults, as bone turnover occurs the bone matrix becomes progressively demineralized which can lead to bone pain and osteomalacia
What are examples of deficiency of vitamin D and who is most at risk? What is the most common cause of toxicity?
-deficiency: rickets and osteomalacia *at risk* -infants and children for rickets elderly: low sun exposure, poor intake of vit D -aging reduces synthesis of cholechalficerol on the skin -decreases renal 1-hydoxylase synthesis in response to PTH -Disorders affecting the parathyroid, liver, and/or kidney will impair synthesis of the active form of the vitamin toxicity -wont occur from sunlight -dietary ingestion: -body holds onto vit D similar to vit A; mostly likely of all vit to cause toxicity Chylomicron remnants deliver Vit D to the liver and the liver hydroxylates the vitamin to form 25-OH The 25-OH molecule (aka calcidiol) can stimulate some of the same effects as calcitriol
What are examples of other vitamin D functions? (Details of these functions will not be required to be known)
-helps with muscles, cancer, immunity
need to know foods of Vit D
eggs salmon sardines shitake mushrooms milk
What are the different vitamin D vitamers and what forms of vitamin D are in foods?
plants- D2 (ergocalciferol) animals- D3 (cholecalciferol
As covered in class, explain the sequence of events of how vitamin D influences calcium blood homeostasis. This includes its coordination and interaction with hormones and proteins and involves multiple organs.
*Calcitriol and the Kidney* -Calcitriol appears to be involved in the PTH-stimulated reabsorption of calcium and especially phosphorus in the kidney -Calbindin D 28K is thought to play a role in renal calcium -Synthesis of this protein appears to be calcitriol-responsive -Synthesis may be increased by nVDR mechanism -It is a larger version of the calbindin protein of the small reabsorption intestine *Calcitrol to the bone* -PTH alone or with calcitriol leads to mobilization of Ca and phosphorus from bone to maintain blood levels -This may be mediated by calcitriol's effects on bone cell differentiation -Calcitriol can induce bone marrow (stem) cells to become osteoclasts through interaction with RANKL (receptor activator of NF-kB ligand) -Osteoclasts release hydrochloric acid, alkaline phosphatase, collagenase and other hydrolytic enzymes to dissolve bone and release calcium into blood. -Osteoblasts, the cells partly responsible for forming bone, also respond to calcitriol by producing: Collagen, osteocalcin and other proteins involved in bone mineralization
Describe where the different forms of vitamin D originate from and how they are converted in the body to active and inactive forms. Explain the sequence of events of changing the vitamin D structures and the purpose of the conversion of these structures.
*Vit D2 (plants)* -sunlight/UVB radiation converts ergosterol to previtamin D2 -isomerization turns it into ergocalciferol *Vit D3 (animals)* -created from cholesterol in the skin -converted to 7-dehydrocholesterol (stored in skin) -converted by sunlight/UVB radiation to previtamin D3 (precalciferol) -isomerized to vit D3 (cholecalciferol) -DOWNREGULATION: excessive UVB radiation can convert 7-dehydrocholesterol to lumisterol and 24-hydroxylase can convert previtamin D3 to tachyserol *in body* -cholecalciferol diffuses from skin into the blood and transported around the body via DBP -arrives in the liver, and 25-hydroxylase converts it to 25-OH D3 -converted to 1,25-OH-D3 (active form) by 1-hydroxylase -DOWNREGULATION: 24-hydroxylase can convert 25-OH-D3 to 24,25 OH-D3 and 1,25 OH D3 (active) to 1,24,25 OH-D3
rickets
-Infants and Children develop Rickets from lack of vit d -Failure of bone to mineralize. -Epiphyseal (growth plate) cartilage continues to grow and enlarge without replacement by bone matrix and minerals. -Results in bone deformities, bowed legs and rachitic rosary of the rib cage. -Can be caused by dietary deficiency or lack of sunlight or combination -Craniotabes (softening of bones of skull) -Sitting, crawling, and walking are delayed and if individual is active at this time, weight bearing results in bowing of arms, knock-knees or outward bowing
How is nutriture of Vitamin D assessed?
-Need to look at Vit D-No other good indicators -The plasma concentration of 25-OH D3 (calcidiol) is often used as an index of vit D status. -subclinical deficiency: <37 nmol/L -Vit D deficiency: <28 nmol/L Optimal: 80-120 nmol/L -Toxicity: exceed ~375 nmol/L -Serum Ca or P are NOT good indicators of Vitamin D status
Why was the RDA set at a higher level in 2010? For whom is the RDA higher?
-RDA in 2010 when from AL-RDA so value increased: 200 → 600 IU, was based on bone health and what was required to keep Ca/Bone density stable -adults 19-70: 15 ug (600 IU) -adults >70: 20 ug (this is because elderly have less sunlight exposure, decreased efficiency of generation of vit D from skin)
What are the functions and mechanisms of calcitriol? How does calcitriol exert its effects on gene transcription? How does it have nongenomic actions?
-calcitrol (D3) is the main active form of vit D and functions like a steriod hormone *major functions* -to maintain serum Ca and P levels at high concentrations for bone mineralization -maintain Ca homeostasis to support cellular metabolic processes and neuromuscular functions *it performs this function by* -increasing Ca and P absorption in the SI -increasing Ca and P mobilization from bone -increasing Ca and P reabsorption in the kidney *mechanism* -D3 must bind to receptor in order to elicit a response -calcitriol binds to 2 different types of receptors: membrane receptors and nuclear receptors *genomic and non-genomic mechanisms* -nuclear receptors are denoted as Vit D receptors (VDR) -calcitriol binding causes a change in the shape of VDR -VDR forms a heterodimer with RXR and binds to VDRE -results in gene transcription and protein synthesis
In class we discussed the article by Houghton and Vieth in which they compared vitamin D2 to vitamin D3. The authors stated that vitamin D3 is a superior form of vitamin D based on what four differences (discussed in class)?
1. efficacy at rasiting 25-OH-D3 in blood 2. diminished binding of D2 to vit D binding protein 3. shorter shelf life of Vit D2 4. residual biological activity: 24-hydroxylase action in D2 more efficiently reduces biological activity, while D3 can retain activity after being treating by this enzyme
Be able to explain the metabolic changes that would occur in response to *high blood calcium.*
1. high blood calcium 2. lowers pre-PTH via calcetriol *kidney*; calcitrion (from thyroid) decreases PTH production 3. 25-OH-D3 binds to cubulin- megalin receptor in the plasma membrane of proximal tubule of kidney 4. endocytosis into kidney 5. less 25-OH-D3 converted to calcitiol (active) by renal 1-hydroxylase 6. less production calbindin 28K, TRPV5, and ATP-dependent calcium transporter (these help kidney increase reabsorption of Ca) and Ca excreted (lowers blood volume) *bone* 7. PTH and Calitriol travels to the bone 8. decreases expression of RANKL (ligands produced in osteoblasts) 9. RANKL doesnt bind to RANK on osteoclast precuror cells 10. less production of osteoclasts, less bone breakdown 11. FGF23 porudced by osteoblasts and osteocytes: inhibits calcetriol produciton by inhibiting 1-hydroxylase *enterocyte* -dietary sources: bind to acids, sugars which allow it to go into enterocye without inhibitors -plant sources are bound to oxalates and phylates which cause excretion -lowers gene expression by inhbiting calcitrol from binding to VDR-> VDRE -decreased TRPV6, calbindin 9K, and Ca-ATP synthase production -decreased production of calbindins which decrease pericellular absorption (open tight junctions) -decreases endosomla/lysosomal pathway *large intestine* -phylates, oxalates -~5% bacteria can free Ca
Be able to explain the metabolic changes that would occur in response to *low blood calcium.*
1. low blood calcium 2. signals parathyroid gland to release parathyroid hormone (PTH) *kidney* 3. 25-OH-D3 binds to cubulin- megalin receptor in the plasma membrane of proximal tubule of kidney 4. endocytosis into kidney 5. 25-OH-D3 converted to calcitiol (active) by renal 1-hydroxylase 6. stimulates kidneys to produce calbindin 28K, TRPV5, and ATP-dependent calcium transporter (these help kidney increase reabsorption of Ca) *bone* 7. PTH and Calitriol travels to the bone 8. increases expression of RANKL (ligands produced in osteoblasts) 9. RANKL binds to RANK on osteoclast precuror cells 10. production of osteoclasts, which increase HCL production, alkaline phosphatase 11. breakdown of mineral complex, Ca released into blood *enterocyte* -increased TRPV6 increases Ca absorbtion, binds to calbindin 9K, and transported to blood via Ca-ATP synthase -increased porduction of calbindins which increase pericellular absorption (open tight junctions)
Describe how it is digested, absorbed, transported, and stored.
Absorption/Transport -vit D (D2 and D3) from the diet is absorbed from micelles -absorption is by passive diffusion -50% of dietary cholesterol is absorbed -in intestinal cells most of the vit is incorporated into chylomicrons -D3 that is transferred to DBP can be delivered to extra hepatic tissues metabolism in liver -D2 and D3 go to the liver: converted to 25-OH D3 by the enzyme hepatic vit D 25-hydroxylase -once 25-Oh D3 is made, it is exported into the blood where it binds DBP -hapatic 25-hydroxylase is not tightly regulated -circulating levels of 2-OH D3 reflect both intake and exposure to UV light and it is commonly used to assess status -most of the 25-OH-D3 is taken up by kidney -kidney sends to bind, immune cells, and intestine
