Micronutrients Exam 1

Front 1

Describe Dietary Reference Intakes (DRIs)

Back 1

Are established for gender, life‐stage, & conditions
(ex: pregnancy, lactation).

- They reflect average need per day over a period of time *deviation from the average is expected.*

- Are set for healthy people

– currently does not account for acute/chronic disease or repletion of a deficiency or malnutrition.

Front 2

EAR

Back 2

average daily nutrient intake level estimated to meet the requirement of 50% of individuals in a group.

Front 3

RDA

Back 3

level sufficient to meet the requirement of nearly all (97‐98%) individuals in a group.

EAR & RDA reference values based on estimates of nutrient requirements vary among individuals – assumed to approximate a normal distribution. The median of the distribution = estimated average requirement or the EAR. The RDA is set two standard deviations above the median.

Front 4

Adequate Intake (AI)

Back 4

Nutrient level based on observed or experimentally determined approximation of nutrient intake by a group of healthy people when sufficient scientific evidence is not available to calculate RDA.

Front 5

Tolerable Upper Intake Level (UL)

Back 5

- Highest daily nutrient intake level that is likely to pose no risk from adverse effects to most individuals in the general population.

- As intake increase above UL, risk from adverse effects increases. Applies to chronic use – may be based on total intake
(food, water, & supplements) or supplemental form only. Does not apply to individuals treated therapeuticallywith nutrient doses.

Front 6

Factors influencing bioavailability

Back 6

Diet‐related

– Food matrix or structure (bound to components in food)

– Chemical form of nutrient (heme vs non heme iron)

– Interactions among nutrients

– Interactions with food compounds

(inhibitors/enhancers)

– Processing/treatment of food

Host‐related:

– Intestinal factors

– Age

– Physiologic state

Front 7

Phytates

Back 7

- storage form of phosphate in certain plant‐based foods (unrefined cereals, legumes,nuts & seeds).

- In the gastrointestinal tract, phytates bind with certain minerals –> iron, zinc, calcium, and magnesium forming insoluble complexes.

Front 8

Polyphenols

Back 8

Found in most plants –– Involved in pigmentation, growth, and protection from consumption

– Sources: lentils, kidney beans, spinach, oregano, tea, coffee, red wine, and cocoa.

- Polyphenols can interfere with intestinal absorption of nutrients, particularly minerals‐ ex: complexes with nonheme iron.

Front 9

Heme Iron

Back 9

- Found in meats, poultry, fish. Derived from hemoglobin and myoglobin.

- Better absorbed than non-heme iron.

- Heme Fe must be hydrolyzed from the globin portion of
hemoglobin or myoglobin (by Trypsin, pepsin & other proteases)

Front 10

Heme Iron absorption

Back 10

Heme Fe is soluble and is readily absorbed intact through the duodenum by a putative apical

membrane heme receptor

HCP1 = heme carrier protein 1

HRG1 = heme responsive gene-1

Within the enterocyte

Heme oxygenase (HO) can release Fe from heme so it can join the non heme iron and be stored or utilized.

Alternatively, intact heme may be released across the basolateral surface via the heme exporter FLVCR1

(Feline leukemia virus, type C, receptor 1)

Front 11

Non-heme iron

Back 11

Uptake of nonheme Fe by enterocytes is better understood

– Although less effectively absorbed, nonheme Fe is present in a greater range of foods, most typically in the ferric iron (Fe+3) form

– HCl, pepsin & other proteases release Fe from food most Fe is present as ferric iron (Fe+3) in the stomach

– Non-heme Fe must be freed and reduced in the GI

tract for absorption to occur

Front 12

Regulation of Iron absorption

Back 12

Fe balance controlled at point of absorption
– Absorption is closely tied to the level of the body’s
Fe stores
– Absorption is normally low.....~10% with normal Fe
status
– Absorption is increased (~35%) during Fe deficiency

Front 13

DMT1

Back 13

Divalent metal transporter 1 (DMT1)
– Transport protein located on the apical membrane
– Transports Fe+2 across the apical membrane

Front 14

Dcytb

Back 14

Duodenal Cytochrome B - Located on the apical membrane of the enterocyte
– Dcytb reduces Fe+3 to Fe+2

Front 15

Once Fe2+ has been absorbed into the enterocyte it can follow one of these three paths

Back 15

1. The iron can be utilized by the intestinal cell as needed.

2. The iron could be stored in the cell as ferritin. Ferritin uses its feroxidase to convert the ferrous iron back into ferric iron.

3. It can be exported from the intestinal cell through the ferroportin transporter that sits on the basolateral membrane.

Front 16

Ferritin

Back 16

Ft stores Fe. Ferritin contains a ferroxidase that convert Fe2+ to
Fe3+ for deposition & storage within its core. The stored Fe (Fe3+) can be reduced back to Fe2+ & released by Ft if needed by the mucosal or other non-intestinal cells. If not needed, the Fe remains within the Ft molecule and is excreted when the mucosal cells are sloughed off (2-3 d)
– Ferritin synthesis in the intestine is directly affected by Fe status (positive.....more Fe = more Ft)

Front 17

Ferroportin

Back 17

a transmembrane protein that transports iron from the inside of a cell to the outside of the cell.
– transports Fe2+ across the basolateral membrane

Front 18

Hephaestin

Back 18

a transmembrane copper-dependent ferroxidase necessary for effective iron transport from intestinal enterocytes into the circulation.
Oxidizes the Fe from ferrous form (Fe2+) to ferric iron (Fe3+)

Front 19

How does copper deficiency affect iron status?

Back 19

Cu deficiency results in the accumulation of Fe in intestine & liver

Front 20

Transferrin

Back 20

Once across the basolateral membrane, transferrin transports Fe+3 in circulation. Tf transports iron through the blood to various tissues, such as the liver, spleen, and bone marrow. Requires oxidation by Hephaestin (cell membrane) and
ceruloplasmin (intracellular): Both Cu-containing proteins with ferroxidase activity

Front 21

Transferrin Recepter & TfR cycle

Back 21

Transferrin receptor (TfR) is a carrier protein for transferrin.

- It is needed for the import of iron into cells and is regulated in response to intracellular iron concentration.

- Iron uptake depends on the transferrin saturation level.

- For uptake to occur, transferrin binds to the transferrin receptor (TfR) on cell surfaces.

– Contains two subunits that each bind one transferrin molecule

– Following binding, TfR is internalized by endocytosis accumulating in endosomes

– Endosomal pH is lowered to ~5.5, reducing and releasing Fe into cytosol

– TfR and transferrin are recycled back to the cell surface

Front 22

PCBP1 & 2

Back 22

PCBP1 & 2 (Poly C binding protein): Cytosolic metallochaperone proteins
– PCBP delivers cytosolic Fe to ferritin
– PCBP interacts with DMT1 and ferroportin, thus functions as a gatekeeper for Fe import and export

Front 23

Regulation of Iron absorption

Back 23

Fe balance controlled at point of absorption
– Absorption is closely tied to the level of the body’s Fe stores
– Absorption is normally low.....~10% with normal Fe status
– Absorption is increased (~35%) during Fe deficiency

Front 24

Factors that enhance iron absorption

Back 24

Acids, such as ascorbic acid (Vit C) and citric acid

→ Reducing agents: reduce ferric iron (Fe3+) to the more bioavailable form of ferrous iron (Fe2+)

Dietary proteins, such as meats, poultry & fish

→ Amino acids may improve solubility & promote absorption

Amino acids, such as histidine, cysteine, methionine

Enhanced erythropoiesis due to hypoxia, hemorrhage, hemolysis, androgens, cobalt, and low Fe status

Front 25

Factors that inhibit iron absorption

Back 25

Chelators
Polyphenols can reduce Fe absorption by > 60%
Phytates and oxalates bind Fe (and other minerals) forming insoluble complexes
– EDTA (preservative)
– Calcium and phosphorus can inhibit Fe absorption by forming
a Fe:Ca:PO4 complex (300 – 600 mg of Ca given with 18 mg of Fe decreased Fe absorption by ~70%)

Front 26

Endogenous factors

Back 26

Infection/inflammation, Lack of stomach acid, High Fe status

Front 27

Competitors

Back 27

– Zinc, manganese & nickel compete for absorption via DMT1,
so large intakes of one mineral can reduce the absorption of
the other

Front 28

Regulation of Iron Homeostasis

Back 28

Despite environmental abundance, poorly absorbed (likely protective), thus highly conserved once absorbed.

No regulated excretory pathway for iron

Basal or obligatory iron losses include sloughing of dermal cells, sweat, urine, fecal and any type of blood loss including menstruation, blood donation, injury, disease

Cellular and systemic Fe homeostasis should be tightly regulated!

Front 29

Iron as a nutrient

Back 29

Iron is essential for numerous heme & nonheme proteins, but can be toxic to cells if Fe levels are too high

- Pro-oxidant- formation of free radicals

- The most abundant trace mineral in our body & the most abundant mineral on Earth

One of the best studied metals in nutrition and healthRole in oxygen and energy metabolism

Front 30

Hemoglobin (Hb)

Back 30

- Protein in red blood cells that is responsible for delivery of oxygen to the tissues.

- Synthesized in RBCs

- 2/3 of total body Fe is located in our RBCs

- Allows oxygen transport from the lungs to tissues

Front 31

Myoglobin

Back 31

Short-term storage of oxygen in muscle
– Supply oxygen to the demand of working muscles

Front 32

Body iron

Back 32

The average adult human contains ~3-4 g iron
Erythrocyte hemoglobin (~2-3 g iron)
Other iron-rich tissues: liver and spleen

Front 33

Ferrous Iron

Back 33

Fe2+

Front 34

Ferric Iron

Back 34

Fe3+

Front 35

Regulation of Iron Status at the Cellular Level

Back 35

A major mechanism regulating Fe status at the cellular levels Is post -transcriptional regulation of transferrin receptor, ferritin, and other key factors

- Uptake of Fe into cells is proportional to levels of transferrin receptor

- Excess Fe must be stored in ferritin to prevent oxidative damage

- Transcripts of transferrin receptor and ferritin contain: Iron-responsive elements (IREs), stem-loop RNA structures that control stability and translation of mRNAs

- IREs are bound by iron regulatory proteins (IRP1 and IRP2)

- Regulate expression of many important factors in iron transport, utilization, and storage in a coordinated way

Front 36

Low Fe concentration in the cell

Back 36

- Transferrin Receptor is needed, but Ferritin is not

- IRP exists as a 3Fe-4S cluster

- IRP binds to the ferritin mRNA IRE (5’ UTR) which decreases translation/synthesis of ferritin

- IRP binds to the TfR mRNA (3’ UTR) this stabilizes the mRNA leading to increased translation and synthesis of TfR

(-) Ferritin, Ferroportin

(+) DMT1, Transferrin receptor

Front 37

High Fe concentration in the cell

Back 37

- Ferritin is needed, but TfR is not

- IRP exists as 4Fe-4S Cluster

- Reduced binding affinity for IRE

- The 5’ UTR block on Ft synthesis is removed & Ft levels rise

- Concurrently, IRP can no longer bind to the 3’ UTR of TfR and TfR mRNA is rapidly degrade

(+) Ferritin, Ferroportin

(-) DMT1, Transferrin receptor

Front 38

IREs

Back 38

Iron-responsive elements are stem-loop RNA structures that control stability and translation of mRNAs

Front 39

IRPs

Back 39

Iron regulatory proteins bind to IREs and regulate expression of many important factors in iron transport, utilization, and storage in a coordinated way

Front 40

Systemic regulation of iron homeostasis

Back 40

Hepcidin regulates cellular iron by binding ferroportin and inducing its internalization

Front 41

Hepcidin

Back 41

25 amino-acid peptide hormone
– Released during iron-loading, infection, or inflammation
– Synthesized by hepatocytes
Directly interacts with ferroportin (Fpn) in enterocytes, macrophages, and hepatocytes
Fpn internalization and lysosomal degradation decrease Fe transfer to blood

Front 42

Molecular mechanisms of hepcidin regulation

Back 42

1) BMP/HJV Complex: Model of hepcidin regulation by iron stores
in the liver
2) HFE/TfR2 Complex: Model of hepcidin regulation by plasma Tf
“Extracellular signal” = degree of saturation of Tf
3) Inflammation signal: Pathological regulator of hepcidin production

Front 43

Acute-phase response

Back 43

Infection/trauma/burns
Human body initiates an inflammatory response
Cytokines such as interleukin-6 (IL-6) stimulate hepcidin synthesis in hepatocytes
Reduced export of Fe into plasma
Results in defective Fe recycling from macrophages
Decreased Fe availability for erythropoiesis
Cytokines such as IL-1β & TNF-α reduce erythropoiesis by inhibiting erythropoietin (EPO) release
Inflammatory marker, C-reactive protein (CRP): used to assess level of inflammation – will be elevated

Front 44

Anemia of Chronic Disease (ACD)

Back 44

Chronic Inflammation
Chronic inflammatory disorders, such as cancer, Crohn’s
disease, ulcerative colitis, rheumatoid arthritis, leukemia,
chronic infection,,,,,,,
Inflammation leads to cytokine production
Stimulates hepcidin synthesis
Reduces iron export
Serum iron levels decrease
Anemia develops because dietary Fe absorption and Fe
mobilization from body stores are inhibited by
inflammation-induced hepcidin up-regulation
“Anemia of inflammation”

Front 45

Iron function in body - Electron transport and energy metabolism

Back 45

Cytochromes and mitochondrial electron transport chain
– Cytochromes: heme-containing enzymes involved in
mitochondrial electron transport chain (cytochrome b and
c) required for cellular energy production
– Nonheme iron-containing proteins like NADH
dehydrogenase & succinate dehydrogenase are also critical
to energy metabolism

Front 46

Iron function in body - Antioxidant

Back 46

Catalase
- Heme-containing enzyme
- Converts hydrogen peroxide to water and molecular oxygen
- Protect cells against the accumulation of hydrogen peroxide,
a potentially damaging ROS

Front 47

Iron turnover

Back 47

Dietary Fe is important for maintaining long-term Fe status
Daily needs are met by efficient conservation and constant recycling of body Fe
Most Fe entering plasma has come from sites of hemoglobin destruction and sites of ferritin degradation
Heme degradation contributes ~20 – 25 mg of Fe/d
Hemoglobin is degraded by phagocytes of the reticuloendothelial system (liver, spleen, bone marrow)
RBCs live for ~120 d before degradation
– Iron recycling is very efficient ~35 mg being recycled daily

Front 48

Iron excretion

Back 48

Daily losses by adult males ~0.9 – 1.0 mg/d
Daily losses by post-menopausal women ~0.7 – 0.9 mg/d
Losses occur from three main sites:
– Gastrointestinal tract (0.6 mg/d)
– Skin (0.2 – 0.3 mg/d)
– Kidney (~0.08 mg/d)
Daily losses by pre-menopausal women ~1.3 – 1.4 mg/d

Front 49

Iron deficiency

Back 49

Most common nutrient deficiency in the US &
world
Estimated to affect 2 – 5 billion people
Iron deficiency anemia
~ 39% of children < 5 years of age
~ 48% of 5-to-14 year-old children
~ 42% of women in developing countries
Primary causes include:
– Low intake of bioavailable Fe
– High Fe requirement
– Excess blood loss (trauma)
– Pathological infections (intestinal or urinary blood loss)
Iron deficiency can occur “with or without anemia”

Front 50

Levels of Iron deficiency from least to most severe

Back 50

Storage iron depletion
Iron stores are depleted, but the functional iron supply is not limited
Early functional iron deficiency
Before the development of anemia, the supply of functional iron to tissues, including bone marrow, is inadequate such as to impair erythropoiesis
Iron-deficiency anemia
Iron-deficiency anemia occurs when there is inadequate iron to support normal red blood cell formation

Front 51

Symptoms of Iron deficiency without anemia

Back 51

1) Impaired cognitive function
Irreversible impairment of learning and cognition can occur with iron deficiency in children
2) Diminished work capacity
Oxidative energy production
3) Inability to regulate body temperature
Thyroid peroxidase activity (heme-dependent enzyme) for thyroid hormone synthesis
4) Impaired immune function
Myeloperoxidase activity (generating free radical response to infection) & changes in lymphocyte and neutrophil function

Front 52

Symptoms of Iron deficiency anemia

Back 52

Fe deficiency anemia (microcytic, hypochromic):
– Fatigue
– Pica (eating of non-food stuff)
– Pallor of the conjunctiva and skin
– Nails that break easy and spoon-shaped nails

Front 53

Inherited Iron Overload Diseases

Back 53

Hereditary Hemochromatosis
– Genetic disorder of iron metabolism
– Most common Mendelian inherited trait of Northern
Europeans
– Fe is progressively deposited in liver, heart & pancreas
causing extensive organ damage and ultimately failure
Symptoms
– Fatigue, joint pain, abnormal
pigmentation of skin, organ damage
Treatment
– Iron depletion therapies including
phlebotomy and chelation

Front 54

Types of hereditary hemochromatosis

Back 54

1. HFE-related hemochromatosis
- Autosomal recessive mutation of HFE gene
- Slow progressive Fe accumulation in organs- 4th-5th decade of
life
2. Juvenile hemochromatosis
- Autosomal recessive mutations in the Hemojuvelin (HJV) gene
or hepcidin (HAMP) gene
- early onset usually before age 30
3. Transferrin receptor 2-associated hemochromatosis
- Autosomal recessive mutation of TfR gene
4. Ferroportin disease
- Autosomal dominant mutation of ferroportin gene

Front 55

HFE-related hemochromatosis

Back 55

Two mutations (C282Y & H63D) in the HFE gene
account for ~90% hemochromatosis in the US
HFE gene plays a role in regulating intestinal
absorption of dietary iron and with sensing the body’s
iron stores
In US, approximately 1 in 220 Caucasians are
homozygotes for the C282Y mutation
– Non-Hispanic whites-heterozygotes 9.5%
– Non-Hispanic blacks-heterozygotes 2.3%
– Mexican Americans-heterozygotes 2.8%

Front 56

Neurodegeneration with Brain Iron Accumulation

Back 56

A group of genetic neurological disorders characterized by
abnormal accumulation of iron in the brain and progressive
degeneration of the nervous system.
Symptoms
Movement problems, Dementia, difficulty speaking, difficulty
swallowing, muscle problems, seizures, tremor, vision loss, weakness

Front 57

Factors that inhibit calcium absorption

Back 57

Oxalic acid: a common compound in plants such as green leafy vegetables (spinach, beet greens), rhubarb, parsley, carrots, cocoa, sweet potatoes

Phytates: unrefined cereals, legumes, nuts & seeds

Front 58

Calcium interactions with other nutrients

Back 58

Protein:
Protein intake can contribute to urinary calcium excretion
appears to be offset by increased calcium absorption
Sodium:
High sodium intake results in increased renal calcium excretion – a concern if calcium intake is low
Iron:
Calcium content of a glass of milk (~ 300 mg) can reduce nonheme absorption by half. Interaction generally not associated with diminished iron status long term with complex meals that contain iron absorption enhancers.

Front 59

Transcellular Absorption of Calcium

Back 59

Facilitated diffusion - limited capacity (saturable)
Highest absorption efficiency in duodenum – to a lesser extent in the jejunum, absent from the ileum
Vitamin D plays a significant role
Primary absorption mechanism for low Ca2+ intake

Front 60

Paracellular Absorption of Calcium

Back 60

Non-saturable diffusion - linear relationship between intestinal lumen calcium content and absorption
Occurs throughout the intestine
Primary absorption mechanism for higher Ca2+ intake
Calcium movement occurs between enterocytes
Dependent on calcium concentration in intestinal lumen
Appears to be regulated by the permeability of tight junctions
Vitamin D increases production of claudins which appear to promote calcium movement through the intercellular space.

Front 61

Vesicular Calcium Transport Model

Back 61

Calcium uptake via endocytosis - shown to accumulate in lysosomes in the enterocyte
Calcium extruded from the enterocyte via PMCA1b or exocytosis
Based on animal studies, may be an absorptive pathway for calcium

Front 62

Calcium Transport/Distribution

Back 62

In plasma, total calcium consists of:
30-55% is protein-bound calcium (bound to albumin)
5-15% is calcium complexed with small anions (sulfate, citrate, bicarbonate)
~50% is ionized or free ions (unbound)

Front 63

Biological Function of Calcium

Back 63

Free cytosolic calcium levels extremely low compared to ECF levels
Ligand binding to cell surface receptors activates a variety of signaling pathways flux of calcium into cytosol
Cytosolic calcium functions as a second messenger & cofactor for proteins regulating cellular processes such as:Contraction of muscle, Release of neurotransmitters, Secretion of endocrine hormones, Cell proliferation

Front 64

Determining Calcium Requirements

Back 64

Calcium Balance study of adults (19-50y):
Goal of setting calcium requirement for this lifestage is to maintain bone health and neutral calcium balance
No evidence (at this time) that providing more calcium benefits bone health
Slight bone accretion occurs in young adults, however, calcium requirement for this accretion appears low
New DRI for calcium based on Hunt and Johnson (2007) data

Front 65

Determining Tolerable Upper Intake Levels

Back 65

IOM evaluated research to assess relationship between nutrient dose and adverse effect (duration and severity).
NOAEL: highest intake level at which “the
adverse effect” is not observed.
LOAEL: lowest intake level in which an adverse
effect occurred.
UF: uncertainty factors – they account for all
the potential uncertainties in the process of
establishing UL.

Front 66

Describe the photosynthesis of Vitamin D

Back 66

During exposure to sunlight, the high-energy UVB (290-315 nm) penetrates the epidermis and photolyzes provitamin D3 or 7-
dehydrocholesterol (7-DHC) to previtamin D3. Once formed, previtamin D3 undergoes a thermally induced isomerization to vitamin D3 that takes 2-3 days to reach completion. Over 90% of the formation of previtamin D3 occurs in the epidermis. Within the epidermis, highest concentration of 7-DHC found in stratum spinosum & basale layers.

Front 67

Factors That Influence UVB Absorption

Back 67

Melanin
Sunscreen/clothing/barrier
Latitude
Time of Day
Season

Front 68

Dietary Sources of Vitamin D

Back 68

Vitamin D3 = (cholecalciferol) made in the skin, found in animal/fish, egg yolks, supplements
Vitamin D2 = (ergocalciferol) fungal, yeast, supplements
Vitamin D3 and vitamin D2 appear to have similar bioavailability

Front 69

Dietary Vitamin D Absorption

Back 69

Absorptive pathway of vitamin D in the intestine not well understood:
– Assumed to be similar to lipids micelle-dependent solubilization and diffusion into enterocyte, incorporated into chylomicrons
– A small amount of free vitamin D may enter circulation and bind with vitamin D binding protein

Front 70

Vitamin D Binding Protein (DBP)

Back 70

Produced in the liver

– transport protein for vitamin D
- Vitamin D synthesized in the skin readily binds to DBP

- Some vitamin D absorbed from diet may be transported by DBP

- Once hydroxylated by the liver, 25(OH)D is primarily bound to DBP - small amount bound to albumin

Hint 70

DBP vs VDR

Front 71

Vitamin D Metabolism

Back 71

- Vitamin D (from skin and diet) is taken up by the liver

- Hepatic hydroxylation of vitamin D produces the main circulating (inactive) form 25(OH)D

Front 72

Vitamin D Metabolism - Activation of Vitamin D

Back 72

- 25(OH)D (inactive), the main circulating form is primarily bound to DBP.

- 25(OH)D is hydroxylated by renal 1α-hydroxylase (CYP27B1) generating 1,25(OH)2D, the active form.

Front 73

Vitamin D3

Back 73

(cholecalciferol) made in the skin or consumed in diet (animal/fish, supplements)

Front 74

Vitamin D2

Back 74

(ergocalciferol) fungal, yeast

Front 75

Megalin

Back 75

found on the apical surface of renal tubule cells is a receptor for DBP. Promotes the recycling of vitamin D.

Front 76

Regulation of renal 1α-hydroxylase (CYP27B1)

Back 76

(+) PTH, hypocalcemia
(-) FGF23, 1,25(OH)2D, hypercalcemia

Front 77

Role of Vitamin D in Calcium Intestinal Absorption

Back 77

Active form of vitamin D binds to its Vitamin D Receptor (VDR) in cell nucleus, complexes with RXR, binds to Vitamin D Receptor Element (VDRE) inducing the synthesis of TRPV6, calbindin, PMCA1b, and NCX1 in the intestine.

Front 78

Factors that increase renal reabsorption of calcium

Back 78

- Parathyroid hormone (PTH)

- Vitamin D (active form)

- Fibroblast-like growth factor 23 (FGF-23)

- Hypocalcemia

Front 79

Role of 1,25(OH)2D in maintaining calcium homeostasis (Intestine)

Back 79

Vitamin D helps to maintain calcium homeostasis in the intestine by increasing calcium absorption in the intestine. The active form of vitamin D enters the enterocyte from the blood. 1,25(OH)2D then binds to its Vitamin D receptor (VDR) in the nucleus of the enterocyte and activates calcium transport related genes such as TRPV6, calbindin, PMCA1b, and NCX1. This greatly increases the amount of calcium absorbed in the intestine.

Front 80

Role of 1,25(OH)2D in maintaining calcium homeostasis (Kidney)

Back 80

The activation of calcium transport-related genes, such as TRPV5, calbindin, PMCA1b, and NCX1, leads to an increase in renal reabsorption of calcium.

Front 81

Role of 1,25(OH)2D in maintaining calcium homeostasis (bone)

Back 81

- Vitamin D 1,25(OH)2D binds to the vitamin D receptor in the osteoblast
- Ligand within the osteoblast (RANKL) is increased
- RANKL then binds to RANK, the osteoclast precursor
- Binding action triggers the formation of osteoclasts which will then go on to break down old bone tissue. As a result, the bone releases calcium in addition to other minerals. This increases the level of calcium in the extracellular fluid

Front 82

FGF23 role in maintaining calcium homeostasis

Back 82

High levels of the active form of Vitamin D (1,25(OH)2D) will eventually stimulate the production of FGF23 by osteoblasts and osteocytes in the bone.
- FGF23 inhibits parathyroid hormone (PTH) production and secretion.
- FGF23 also decreases 1a-hydroxylase. FGF23’s inhibitory action on PTH and 1a-hydroxylase decreases the activation of Vitamin D in the kidney.

- This slows the breakdown of bone tissue helping to regulate that process.
- FGF23 also increases calcium reabsorption in the kidney by increasing TRPV5 synthesis.

- Prevents excessive loss of calcium and helps to maintain calcium homeostasis.

Front 83

FGF23 increases calcium reabsorption in the kidney by increasing

Back 83

TRPV5 synthesis

Front 84

What happens when 1,25(OH)2D binds Vitamin D receptor (VDR) in the nucleus of the enterocyte

Back 84

TRPV6, calbindin, PMCA1b, and NCX1 are increased

Front 85

TRVP6

Back 85

Intestine

Front 86

TRVP5

Back 86

Kidney

Front 87

PCBP

Back 87

PCBP1&2(PolyC binding protein): Cytosolic metallochaperone proteins

– PCBP delivers cytosolic Fe to ferritin

– PCBP interacts with DMT1 and ferroportin, thus

functions as a gatekeeper for Fe import and export

Front 88

HCP

Back 88

Heme carrier protein

Front 89

HRG

Back 89

Heme responsive gene

Front 90

Model of hepcidin regulation by iron storesin the liver

Back 90

BMP/HJV Complex

Front 91

Model of hepcidin regulation by plasma Tf “Extracellular signal” = degree of saturation of Tf

Back 91

HFE/TfR2 Complex

Front 92

Genomic function of Vitamin D

Back 92

– 1,25(OH)2D - VDR complex binds toVDREs (specific DNA promotersequences)

– Many genes regulated by vitamin D

Front 93

Nongenomic functions of Vitamin D

Back 93

– Rapid response to 1,25(OH)2D

– Pathways have been identified in whichvitamin D mediates a rapid response

–triggers signaling cascades

– Mechanism of action not wellunderstood though appears to be amembrane mediated response

Front 94

Vitamin D insufficiency

Back 94

Myopathy

Diabetes

Neurological diseases

Coronary disease

Hypertension/arteriosclerosis

Autoimmune diseases

Front 95

24 hydroxylase

Back 95

Turns active or inactive Vit D into inactive form to be excreted

(+) Catabolism of 1,25(OH)2D

Front 96

24 hydroxylase is regulated by

Back 96

(+) FGF23, 1,25(OH)2D

(-) PTH

Front 97

Intracellular Calcium Signaling

Back 97

Free cytosolic Ca levels are much lower than extracellular fluid

Cytosolic calcium levels must be maintained at a low level because it functions as a second messenger & cofactor for proteins regulating cellular processes such as:

- contraction of muscles (cramps, spasms)

- release of neurotransmitters

- secretion of endocrine hormones

- cell proliferation (cancer)

Front 98

HFE

Back 98

hemochromatosis protein

Front 99

HJV

Back 99

hemojuvelin (gene)

- may be mutated in Juvenile hemochromatosis

Front 100

hemochromatosis

Back 100

iron overload

Front 101

BMP

Back 101

Bone morphogenetic protein; part of BMP/HJV Complex