Vitamin D

What is the Genomic Effect of Dihydroxycholecalciferol (1,25-(OH)2-D3)?

1. Binds to Vit. D Receptor (VDR) 2. Travels to the Vit. D Response Element (VDRE) 3. Binds VDRE as a Heterodimer along with 9-Cis-Retionic Acid/Retinoid X Receptor (RXR) Complex 4. Heterodimer promotes Histone Acetylation and Methylation to promote transcription - Note: This only occurs if Vitamin D is bound to VDRE. Unlike Steroid Receptors, if Vitamins D or A are not bound to their receptors, they still go to the Nucleus as a VDRE/RXR Receptor Heterodimer, but instead Repress DNA Transcription by Recruiting Repressors such as Histone Deacetylases 5. Stimulates Terminal Differentiation of Osteoclasts as well as Stimulates Osteoblasts to release signals that cause Osteoclasts to break down Bone and Mobilize Calcium Note: This is a Slow acting response

Vitamin D protects against cancer by what 2 mechanisms?

1. Causes G0/G1 arrest by upregulating P21, waf/cip1, and p27/kip1 2. Stimulates G2/M Arrest by inducing Growth Arrest/DNA Damage Gene (GADD45a)

Calcitonin has 3 signaling actions, which are?

1. Small Intestine-->Dec. Ca2+ Reabsorption (most minor effect) 2. Kidney-->Increase Ca2+ excretion in Urine and Increase degradation of 1,25-(OH)2-D3 (minor effect) 3. Bones-->Osteoblats deposit more Calcium (MAJOR Effect)

What are the 3 signaling actions of the active form of Vitamin D (1,25-(OH)2-D3 or Dihydroxycholecalciferol)?

1. Small Intestine-->Reabsorb more Calcium 2. Kidney-->Reabsorb more Calcium, excrete less Ca2+ in Urine-->Osteocalcin synthesis increases to cause this effect 3. Bones-->Signals Osteoclast Resorption of Bone

What are the 4 Non-Bone Related Fxns of 1,25-(OH)2-D3?

1. Stimulates Innate Immunity 2. Inhibits Adaptive immunity 3. Lowers BP (via Renin Inhibition) 4. Stimulates Tumor Suppressor Signaling Proteins (G0/1 Arrest via p21, waf/cip1, and p27/kip1 + G2/M Arrest by GADD45a)

What 2 ways are used to Dx Celiac Disease?

1. Test for Glucose Absorption 2. Test for Transglutaminase

How does 1,25 (OH)2 D3 suppress T-Cell Activation?

1. Toll-Like Receptors (TLRs) stimulate Macrophages to synthesize 1,25-OH2-D3 2. 1,25-OH2-D3 activates the Macrophages and de-activates Activated T-Cells This stops massive progressions of T-Cell Activation and prevents Sepsis

Which of the following is the Active Form of Vitamin D2? A. Cholecalciferol B. 1,25 Dihydroxyergocalciferol C. 1,25 Dihydroxycholecalciferol D. Ergocalciferol

B. 1,25 Dihydroxyergocalciferol

Which of the following is the Active Form of Vitamin D3? A. Cholecalciferol B. 1,25 Dihydroxyergocalciferol C. 1,25 Dihydroxycholecalciferol D. Ergocalciferol

C. 1,25 Dihydroxycholecalciferol

The prefix "Ergo-" refers to which Vitamin? A. Vitamin A B. Vitamin C C. Vitamin D2 D. Vitamin D3

C. Vitamin D2

Cytosolic D Binding Protein (cDBP) is used for Vitamin D uptake into _______ (which Lipoprotein)?

Chylomicrons

What is the name of the Binding Protein which Dietary Vitamin D binds to within Enterocytes/which then transports Vitamin D in the Blood to the Liver via incorporating it into Chylomicrons?

Cytosolic D Binding Protein (cDBP)

Which of the following is the Parent Form of Vitamin D2? A. Cholecalciferol B. 1,25 Dihydroxyergocalciferol C. 1,25 Dihydroxycholecalciferol D. Ergocalciferol

D. Ergocalciferol

The prefix "Chole-" refers to which Vitamin? A. Vitamin A B. Vitamin C C. Vitamin D2 D. Vitamin D3

D. Vitamin D3

Higher levels of Melanin cause you to have an __________ (increased or decreased) ability to use UV light to convert 7-Dehydrochoelsterol to Cholecalciferol (Animal D3)?

Decreased Melanin levels have an Inverse Relationship with ability to use UV light to convert 7-DHC to Cholecalciferol (D3)

PTH impacts Osteopotegerin (OPG) and RANK Ligand in what way?

Downregulates OPG and Upregulates RANK Ligand Causes Osteoclast Maturation/Differentiation

CD-36, Niemann-Pick C1-Like 1 (NPC1L1), and SR-B1 are used for the Dietary Absorption of Vitamin D into _______ (what cells)?

Enterocytes of the SI

What signaling cascades does Vitamin D promote and is this response Genomic or Non-Genomic?

GPCR-->AC->cAMP-->PKA or GPCR-->PLC-->IP3 + DAG - IP3 signals Ca2+ release from ER - DAG activates PKC which drives Ca2+ released by IP3 to the membrane of intestinal cells for release into the Blood (I think?) - Also activate Calbindin D (Ca2+ binding protein in Ca2+ Transport) - Also Activate Calcium ATPases which drive Calcium out of the Cells and into the Blood Non-Genomic

What 2 AAs is Gluten enriched in?

Glutamine (Gln) and Proline (Pro) Due to a Transglutaminase enzyme defect

ABCA1 and ABCG2 are transporters used for Vitamin D uptake into _______ (which Lipoprotein)?

HDLs This occurs AFTER dietary Vitamin D has been absorbed by CD-36/NPC1L1/SR-B1 into SI Enterocytes

What 2 genes are involved in Celiac Disease?

HLA DQ2 and HLA DQ8

Vitamin D inhibits Hypertension by?

Inhibiting Renin Reduced Ang II and Aldosterone impacts on BP

Scavenger Receptor Class B Type 1 (SR-B1) has a _________ (Low or High) Specificity for ligands?

Low Specificity for ligands This allows SR-B1 to bind many types of Lipophilic compounds transported within Micelles and cause them to be taken up into Enterocytes

PTH causes Osteoblasts to release hormonal signals to Osteoclasts via a ________ (endocrine/juxtacrine/paracrine) mechanism?

Paracrine

What is the chemical name for the 1 main forms of Vitamin A? Give both the Parent Form and Active Form(s)

Parent Form: Retinol Active Forms: 1. Retinol (Alcohol/Hydroxy) 2. Retinal (Aldehyde) 3. Retinoic Acid (-COOH) Retinol is Oxidized to Retinal, which is then Oxidized to Retinoic Acid. Each step on the Oxidation ladder is Irreversible.

Scavenger Receptor Class B Type 1 (SR-B1) has what function?

SR-B1 is used in the uptake of Vitamin D from the Diet Vitamin D is taken up by Micelles, and transported to the SI Lumen, where it is released and binds to SR-B1 for uptake into Enterocytes After uptake by Enterocytes, Vitamin D binds to Cytosolic D Binding Protein (cDBP) and incorporates them into Chylomicrons, after which it is transported to the Liver

What is the name of the receptor which Dietary Vitamin D binds to in the SI Lumen for uptake by Enterocytes?

Scavenger Receptor Class B Type 1 (SR-B1)

25-Hydroxylase converts Vitamin D from its' Parent Forms (Ergo/Cholecalciferol) to its' Circulating Form (25-OH-D3=Calcediol) inside what organ?

The Liver

What receptor does Vitamin D use to activate Macrophages?

Toll Like Receptors (TLRs)

What does Transcalciferin do?

Transcalciferin (Vitamin D Binding Protein) transports Cholecalciferol (D3) produced endogenously by the Skin + UV light within the Blood so that it can reach the Liver

Compare the roles/functions of Transcalciferin and Cytosolic D Binding Protein (cDBP) in the transport of Vitamin D to the Liver

Transcalciferin - Binds to ENDOGENOUSLY PRODUCED Vitamin D from the Skin, and transports it to the Liver within the Blood Cytosolic D BP (cDBP) - Binds to DIETARY Vitamin D in the Cytosol of Small Intestinal Cells (Enterocytes) and transports it in the Blood to the Liver

What converts 7-Dehydrocholesterol to Cholecalciferol (Animal Vitamin D3)?

UV Exposure

Calcitonin impacts Osteopotegerin (OPG) and RANK Ligand in what way?

Upregulates OPG and Downregulates RANK Ligand Prevents Osteoclast Maturation/Differentiation

Estrogen impacts Osteopotegerin (OPG) and RANK Ligand in what way?

Upregulates OPG and Downregulates RANK Ligand Prevents Osteoclast Maturation/Differentiation

What are the chemical names for the 2 main forms of Vitamin D? Give both the Parent Form and Active Form

Vitamin D2 - Parent Form: Ergocalciferol - Active Form: 1,25 Dihydroxyergocalciferol Vitamin D3 - Parent Form: Cholecalciferol - Active Form: 1,25 Dihydroxycholecalciferol

Cytosolic D Binding Protein (cDBP) has what function?

cDBP binds to dietary Vitamin D inside Enterocytes and inc it to the Liver

How does 1,25-D3 Promote Innate Immunity?

- Activates macrophages by Toll-Like Receptors (TLRs) - Active Macrophages use 1α-Hydroxylase to convert 25-OH-D3 (Calcidiol) to its active form 1,25-(OH)2-D3 (Calcitriol) - 1,25-(OH)2-D3 (Calcitriol) induces the expression of Cathelicidin (an antimicrobial peptide) - 1,25-(OH)2-D3 (Calcitriol) decreases EXPRESSION of already active T-Cells

How does 1,25-D3 Suppress Adaptive Immunity?

- Inhibits dendritic maturity - Inhibits dendritic cell ability to present antigens to CD4 cells - Inhibits proliferation and differentiation of CD4 cells into Inflammatory TH1 and TH17 cells - Stimulates the production of Non-Inflammatory TH2 and Treg cells

How does Vitamin D act as an antibacterial agent as part of the INNATE Immune Response?

- Microorganisms bind to Toll-Like Receptors (TLR) on the membrane of Macrophages - Toll-Like Receptors (TLR) stimulate 1α-Hydroxylase in the Macrophage to make active 1,25-Vitamin D3 - 1,25-D3 signals the nucleus of the macrophage to increase the formation of proteins called Cathelicidins - Cathelicidins are a set of proteolytic enzymes that degrade the bacterial cell wall - Vitamin D3 is converted to its active 1,25-D3 form by 1α-Hydroxylase in the Macrophage - 1α-Hydroxylase is stimulated by microbes binding to Toll-Like Receptors (TLR) on the Macrophage) - Active 1,25-D3 stimulates the Macrophage's Nucleus to produce Cathelicidins - Cathelicidins are a set of proteolytic enzymes that degrade the bacterial cell wall - This is part of Vitamin D's STIMULATION of INNATE IMMUNITY

How does Vitamin D act as part of the ADAPTIVE Immune Response?

1,25-D3 has a direct effect on T-Helper Cells: 1. Downregulates TH1 and TH17 cells - These two cell types release inflammatory factors 2. Upregulates TH2 and Treg cells - These two cell types are less inflammatory T-Cells 3. Downregulates dendritic cell maturity - Dendritic Cells inhibited from presenting antigens to CD4 cells When Autoimmune Diseases cause inflammatory responses: - Vitamin D downregulates (TH1/TH17) promoted inflammatory responses - Vitamin D upregulates (TH2/Treg) non-inflammatory responses - So Vitamin D both prevents inflammation in autoimmune diseases and helps promote non-inflammatory immunity

In Celiac Disease, Vitamin D helps because?

1,25-OH2-D3 activates non-inflammatory TH2 Cytokines + inhibits inflammatory TH-1 Cytokines

What enzyme activates the circulating form of Vitamin D (25-OH-D3 Calcediol), what is the name of the activated form, and in what organ does this occur?

1α-hydroxylase (CYP27B1) 1,25 (OH)2-D3 Dihydroxycholecalciferol The Kidney

What is the enzyme that activates Vitamin D, and what are the 2 ways of regulating it?

1α-hydroxylase (CYP27B1) Regulation: 1. PTH ACTIVATES 1α-hydroxylase (CYP27B1) and is released in response to Low Ca2+ Levels in the Blood, and inhibits 2-Hydroxylase (CYP27B1) PTH Release is inhibited by negative feedback by the active form of Vitamin D (1-25(OH)2-D3 or Dihydroxycholecalciferol) 2. Osteocyte/Osteoblast release Fibroblast Growth Factor 23 (FGF23) in response to high levels of active D3 (Dihydroxycholecalciferol) FGF23 does 2 things: A. Inhibits 1α-hydroxylase (CYP27B1) B. Activates 24-Hydroxylase (CYP24A1) which can then convert circulating 25-OH-D3 into 24,25 (OH)2-D3 which is an Inactive Form, and also convert the active form 1,25(OH)2-D3/Dihydroxycholecalciferol) into 1,24,25 (OH)2-D3 which is excreted

What enzyme converts Vitamin D from its' Parent Forms (D2-->Ergocalciferol; D3-->Cholecalciferol) into its Circulating Form (25-OH-D3=Calcediol)?

25-Hydroxylase Found in the Liver

1α-hydroxylase (CYP27B1) converts _______ (hint: circulating form) to ________ (hint: active form) within the ______ (hint: Organ)?

25-OH-D3 (Calcidiol) 1,25-(OH)2-D3 (Dihydroxycholecalciferol) Kidney

What is the name of the direct precursor intermediate in the Cholesterol Synthesis Pathway which is used to form Vitamin D?

7-Dehydrocholesterol

UV Exposure converts ___________ (Intermediate in Cholesterol Synthesis Pathway) to _________ (Animal Vitamin D3)?

7-Dehydrocholesterol Cholecalciferol (Animal D3)

PTH and FGF23 (released by Osteoblasts/cytes) have opposite effects on which 2 enzymes?

A. 1α-hydroxylase (CYP27B1) - PTH-->Activates - FGF23-->Inhibits B. 24-Hydroxylase (CYP24A1) - PTH-->Inhibits - FGF23-->Activates

Which of the following is the Parent Form of Vitamin D3? A. Cholecalciferol B. 1,25 Dihydroxyergocalciferol C. 1,25 Dihydroxycholecalciferol D. Ergocalciferol

A. Cholecalciferol

Does Vitamin D downregulate or upregulate the following 4 T-Cells? Also indicate whether these cells are inflammatory or non-inflammatory immune mediators. A. TH1 B. TH2 C. TH17 D. Treg

A. TH1-->Downregulated (inflammatory) B. TH2-->Upregulated (non-inflammatory) C. TH17-->Downregulated (inflammatory) D. Treg-->Upregulated (non-inflammatory)

Compare these 2 Vitamin D transporters: A. Cytosolic D Binding Protein (cDBP) B. ABCA1/ABCG2

A. cDBP-->Incorporates Vitamin D into Chylomicrons B. ABCA/ABCG2-->Incorporate Vitamin D into HDLs