Micro - Exam 1 Flashcards
ZnT
Transports zinc out of cytosol (into ECF, organelles, vesicles)
ZIP
Transports zinc into cytoplasm (from ECF, organelles, vesicles)
Metallothionein (MT)
- Zinc storage protein
- Accept and donate zinc
- Binds other metals
- Redox function
- Regulated by MTF-1 (Zn binds MTF1 which up-regulates genes producing MT)
Zinc pools and why they are necessary
- MT
- Intracellular organelles
- Endosomes and lysosomes
Because minerals may react with ROS, may have unintended consequences (deregulating genes, etc), and for osmotic purposes
Zinc sensing (response to high intracellular zinc)
- Under high intracellular Zn, Zn binds MTF-1 (a transcription factor) which up-regulates genes to produce more proteins (MTs) for zinc storage
- ZIP4 ubiquitination and degradation; up-regulation of ZnT
Zinc sources
Food (complexed with proteins and nucleic acids), supplements, and endogenous (bile secretions are reabsorbed – enterohepatic circulation)
Foods: meat, dairy, beans, nuts
Zinc absorption (3 ways)
- Carrier mediated (ZIP4, DMT1)
- Chelation by amino acids
- Paracellular diffusion
Low/high zinc in diet and absorption bioavailability
Low: transport through specific transporter is efficient (bioavailability is high)
High: low bioavailability due to saturated transporters
Zinc absorption inhibitors
Phytate: zinc forms insoluble complexes with phytate
Oxalate
Large supplemental doses of iron and calcium (why?)
Zinc absorption enhancers
- Gastric acid (digest food matrixes and reduce minerals to necessary oxidation state)
- Chelation with amino acids and other organic acids
Zinc sensing (response to low intracellular zinc)
- Free (unbound to Zinc) KLF-4 transcription up-regulates ZIP4 gene transcription
Zinc functions
- Used in proteins for structure
- Used in zinc fingers for gene regulation
Assessment of Zinc status
- Plasma/serum concentration
- Hair/nails
- Urinary excretion
- MTs
Copper sources
- Food (widely distributed), gastrointestinal secretions
Copper absorption
- Transported through CTR1 and DMT1
ATP7A defects
Copper-transporting ATPase transports intracellular copper in the enterocyte to golgi for export into circulation
- defects cause Menkes disease – build up of copper in enterocyte and copper deficiency
Copper excretion
- Excreted through bile
- Urine, hair, nails, semen
Copper functions
- Iron redox
- Antioxidant
- Electron transport
- Gene expression
- Enzymes
Causes of copper deficiency
- Zinc supplementation
- Gastrointestinal surgery
- DMT1 competition
- Malabsorption
- Menkes disease (ATP7A defect)
How do zinc supplements cause copper deficiency?
- Zinc up-regulates MT
- MT has higher affinity for Copper
- Enterocyte gets sloughed off
Chromium deficiency
- Impaired glucose tolerance because chromium is used to increase insulin response
- Chromium is widely available in foods
Flouride
- Stimulates osteoblast proliferation
- Increases tooth enamel resistance to demineralization by acid
Iodine basics
- Used in synthesis of thyroid hormone
- Concentrations in food reflective of soil levels
Iodine deficiency
With low iodine, TSH is not suppressed, so build up of thyroglobulin occurs and thyroid gets larger –> hypothyroidism
Iron functions
- oxygen transport (hemeoglobin/myoglobin)
- electron transport (cytochrome) going from reduced to oxidized forms
- antioxidant
Heme iron (basics and absorption)
- From flesh sources
- Transported into enterocyte as heme
Non-heme iron (basics and absorption)
- From flesh AND plant sources
- Must be reduced from Fe3+ to Fe2+ by brush border reductases (DCYTB1)
- DMT1 co-transport with protons into enterocyte
Non-heme iron enhancers
- Acids (reduction, chelation, substrate for DCYTB1)
- Meat factor (cysteine is iron ligand?)
Inhibitors of non-heme iron
(reduce solubility and prevent reduction)
- Phytate (but iron liberated when fermented)
- Oxilates
- Polyphenols
Iron in the enterocyte
- Bound to chaperone protein, organic molecules
- Bound to ferritin (storage protein)
Iron assessment
- Ferritin (storage protein)
- Hemoglobin or hematocrit
- %transferrin saturation
- Dietary intake/forms
Iron LOSSES
- No physiology excretion mechanism
- Lost via sweat, urine, skin cells, shedding of epithelia
- Menstruation
- Bleeding and blood donation
Iron transport out of enterocyte
- Fe2+ gets transported via ferroportin
- Bound to transferrin (for transport in plasma)
- Ferroportin regulated by hepcidin
Hepcidin
- Protein made in liver to regulate iron absorption
- Hepcidin causes ferroportin to be internalized by enterocyte and sloughed up
- Up-regulated with adequate iron stores (saturated transferrin)
- Down-regulated with low iron stores
Ferritin vs Transferrin
Ferritin = iron storage protein Transferrin = binds iron for transport in the blood
heme oxygenase
- degrades heme and liberates iron
Active vitamin D
- 1,25(OH)2 D3
- Tightly regulated, poor biomarker for assessment
Metabolic pathway of Vit D
- Vitamin D3 from skin/diet enter body
- Gets converted to 25(OH)2D3 by 25-OHase
- 25(OH)D3 gets converted to 1,25(OH)2D3
Activators/inhibitors of production of 1,25(OH)2D3
Activator: low calcium, PTH
Inhibitors: 1,25(OH)2D3
Main function of Vitamin D (calcium absorption)
Increase absorption of calcium!
- 1,25(OH)2D3 binds VDR and increases expression of a calcium channel and increases expression of calbindin (which mediates transport of calcium from luminal to basolateral side of enterocyte)
Why do you not get Vit D toxicity from sunlight?
- Many regulatory steps
- UVB converts substrate into various inactive form
Storage form of Vitamin D
25(OH)D3 found mostly in liver and fat – great for status assessment
Calcium sensing
- Calcium sending receptor (CasR)
- Located all over body but most importantly in parathyroid gland
- Calcium sensing inhibits PTH secretion
PTH and Calcium
PTH increases plasma calcium
Effect of low vitamin D (and low Ca) on PTH
Plasma Ca is low, so CasR does not inhibit PTH. PTH is produced and secreted and increases plasma Calcium through variety of mechanisms
How does PTH increase plasma Ca? (two main ways)
- Liberates Ca from bone
2. Increases Ca absorption through stimulating Vitamin D into active form
Calcium absorption (transporters, factors influencing)
- Through calcium channel
- Calbindin mediates transport of calcium from luminal to basolateral side of enterocyte
- Dose, matrix, inhibitors (phytate/oxalate), other divalent cations, gastric acid
Calcitonin
Tones down calcium by slowing down bone resorption (inhibits osteoclasts)
Refeeding syndrome
Malnourished -> cells are intracellularly depleted of phosphorous -> given glucose -> insulin -> drives glucose and other stuff into cells -> start to make ATP -> phosphorous levels in blood go dangerously low -> fatality
Magnesium absorption
Mostly paracellular absorption!
Vitamin D binding protein (DBP)
- In blood, Vit D is picked up by DBP
- Free vitamin D is more bioavailable than bound
Magnesium basics
- Related to diabetes
- Related to hypertension (relaxes vascular smooth muscle)
- Necessary for metabolism and generation of ATP
ATP7B and defect
- Copper transporter in liver cells export copper to golgi for packaging on ceruloplasmin for secretion to serum and into bile for excretion (under high levels)
- defect causes Wilson’s disease, a condition with reduced ceruloplasmin and biliary copper secretion
Se assessment
- Gpx activity - function
- sel P - status
