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Digestion and Absorption of Minerals I

Digestion and Absorption of Minerals I. (Unifying principles that apply to all minerals). Digestion. Preparing for absorption Liberating minerals from a bound state to an aqueous phase Digestive enzymes Bile acids and salts that work with digestive enzymes (e.g., lipases).

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Digestion and Absorption of Minerals I

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  1. Digestion and Absorption of Minerals I (Unifying principles that apply to all minerals)

  2. Digestion • Preparing for absorption • Liberating minerals from a bound state to an aqueous phase • Digestive enzymes • Bile acids and salts that work with digestive enzymes (e.g., lipases)

  3. Purpose of digestion to mineral nutrition Minerals in a food source are locked within a matrix composed primarily of proteins, complex carbohydrates and fats The purpose of digestion is to render large composite molecules into smaller manageable units…minerals are liberated during this process Digestive processes consists mainly of hydrolytic enzymes that break chemical bonds between modular units without total destruction (metabolism) of the liberated components Products of the digestate aid in the solubilization and absorption of minerals

  4. Digestive Enzymes (hydrolases) Enzyme Location Target Action I II Phase I is primarily salivary and pancreatic secretions Phase II involves enzymes on the surface of absorbing cells

  5. Critical factors in Mineral Absorption • Absorption tends to beselective for the mineral • (makes finding a unified mechanism more difficult) • A deficiency increases the fraction of that mineral absorbed • (absorption is tunedto internal bodily needs) • Certain food chemicals (e.g., phytate, oxalate) lower absorption by tying up the mineral • There is competition for absorption machinery • Metal ions antagonism (Cu-Zn; Zn-Fe; etc.) occurs at ion channels during the transmural passage phase of absorption • Vitamin dependency is seen with Vitamin D and C that regulate body load of Ca+2 and Fe2+respectively • Absorptive cells excrete factors that aid in the solubility of metal ions • Some transport proteins are in vesicles that fuse with the membrane and move vectorially within the cell

  6. Steps in mineral absorption 1. Transport through the luminal (apical) cell membrane, i.e., start of transcellular 2. Handling within the enterocyte, i.e., mediate transcellular 3. Transport through the antiluminal basolateral membrane into the circulation, i.e., end of transcellular. 4. Transport between the cells, i.e., paracellular Only metals in an aqueous phase can be transported into the enterocyte

  7. Solubility and Metal Ion Absorption Two categories of ingested metal Ions 1. Solubility not dependent on pH Examples: Na+, K+, Mg2+, Ca2+ 2. Solubility pH dependent Examples: Cu2+, Fe2+, Mn2+, Zn2+ Category 1 metal ions are soluble throughout the gastrointestinal pH range (1-8) Category 2 metal ions are soluble in acid, but form insoluble hydroxy-polymers at neutral or alkaline pH.

  8. Ca Ca Ca Mucosal Side Fe A large fraction of the iron can be trapped (sequestered) within the cytosol of the enterocye) Fe Fe Microvilli Apical surface Enterocyte Basolateral Surface (antiluminal surface) To access the serosal side, the mineral must pass either through the enterocyte (transcellular 99%) or the junction between enterocytes (paracellular <1%)) Serosal Side

  9. Role of Vesicles in the Regulation of Mineral Absorption Resting Cell Absorbing Cell Vesicles are internal membrane compartments that move between the cytosol and membranes. This movement is regulated by external factors Vesicles contain the transport proteins that absorb the mineral into the lumen of the vesicle and bring it into the cell Vesicles that have fused with the membrane are positioned to absorb minerals. Absorption thus depends on the number of vesicles that fused with the membrane.

  10. MACROMINERALS Monovalent cations, Na+, K+ Monovalent anions, Cl- Divalent cations, Ca2+, Mg2+ Complexes, HPO4=, HCO3-

  11. Rules that apply to the absorption of Macrominerals Rule 1: Macrominerals in general enter intestinal cells through transport portals designated for the mineral (major) or between cells (minor). Rule 2: The energy for entry is provided by a concentration gradient across the membrane or by hydrolysis of ATP (active transport) Rule 3: Electroneutrality is sought in the operation of membrane co-transporters

  12. Macrominerals Na+, K+, Cl-, HPO4-, Mg2+, Ca2+ The macrominerals for the most part rely on diffusion controlled mechanisms combined with specific channel proteins to pass into the system. Gradients across the membrane can be driven by unidirectional and bidirectional ATPase enzymes Example Na+/K+ ATPase Ca2+/H+ ATPase

  13. Properties of Macrominerals Relative to Absorption 1. Monovalent ions exist mostly as free ions 2. Monovalent ions are unable to form stable complexes 3. Divalent ions exist partially as free ions 4. Divalent ions are more apt to form complexes with proteins and organics 5. Complexes exist mainly as free ions

  14. Absorption of Sodium and Chloride Blood Apical (lumen) side Na+ Glucose cotransporter Glucose Na+/K+ ATPase Amino acids Amino acid transporter 3Na+ ATP ase 2K+ Na+ Na+/H+ antitporter H+ H+ Carbonic anhydrase HCO3- H+ + H2CO3 HCO3- H2O Anion antiporter CO2 CO2 Cl- Intestinal Enterocyte

  15. Calcium and Magnesium

  16. Microvilli Mucosal surface [import] (channel proteins, ATPase enzymes, reductases) Cytosol [storage] (transport and storage proteins, vesicles) Serosal surface [export] Three stages in intestinal absorption at the cellular level

  17. Calcium absorption is the sum of saturable and unsaturable processes 1. Solubility depends on dietary source 2. CaHPO4 is 18 time more soluble than CaCO3 3. Solubility also depends on pH 4. Transcellular and paracellular transport processes 5. Transcellular proximal intestine saturable, regulated 6. Paracellular throughout intestine unsaturable, unregulated 7. Vitamin D is the major regulator of transcellular calcium entry 8. Calcium channels in brush border and apical membranes appear to have a vitamin D-sensitive element

  18. 45Ca 45Ca 45Ca Ca Ca Ca Ca Ca Ca Ca Ca Ca Everted Sac and Intestinal Loop Technique to measure Ca2+ Absorption In situ Intestinal Loop Inverted sac Absorption is the amount of Ca2+ effusing with time as measured at different concentrations of Ca2+ Transcellular movement of Ca2+ into the sac is a metabolically active process requiring oxygen and occurs against a concentration gradient. Absorption is the sum of two processes: saturable and non-saturable

  19. Ca2+ Cat1 Activate transcription of Cat1 and calbindin Intestine Calbindin Calcitriol Serum Resorption Ca2+ Ca3(PO4)2 Decrease Excretion Activate osteoclasts Activate hydroxylase Bone 1,25-OH D3 (Calcitriol) Ca2+ PTH Kidney Liver 25-OH D3 Parathyroid PTH Cholecalciferol

  20. In situ intestinal loop experiment showing Ca2+ absorption cannot be due to simple diffusion, but is the sum of two processes, saturated and unsaturated % absorbed = % of total sac 45Ca that effused out 1 mM 100 10 mM Total % Abs 25 mM Unsaturable 100 mM 50 Saturable 200 mM Total = sum of saturated and unsaturated at each time point Time

  21. Vitamin D deficient rats Duodenum -Vit D - Vit D + 1,25-(OH)2-D3 100 100 Calcium Absorbed Non-Saturable 50 50 Saturable 0 0 0 0 100 200 100 200 Dietary Calcium Dietary Calcium

  22. Duodenum Jejunum Ileum 100 Non-saturable 50 Saturable Saturable 0 0 0 0 0 0 100 200 100 200 100 200 Calcium Instilled, mM Uptake in ileum is by diffusion only; it is, therefore, not regulated by vitamin D. Thus, most of the Ca2+ is absorbed in the duodenum.

  23. ADca ([Ca]1 – [Ca]2) F = L Ficks Law of diffusion: The rate of diffusion of an ion at steady-state transmembrane flux varies inversely with path length and directly with area and concentration gradient A = 80 m2 L = 10 m Dca = 3 x 10-3 cm2/min Adolph Fick after Bronner Based on Fick’s law, the expected diffusion rate of Ca across the intestinal cell is 96 x 10-18 mol/min/cell. Rate observed in the laboratory is 70 times greater at Vmax, which means duodenal cells have factors that enhance self diffusion of Ca Possible factor is Calbindin, a small (9 kD) Ca-binding protein

  24. Search for the Vitamin D sensitive Factor • Calbindin (9 kd cytosolic Ca-binding protein) • CaT1 (a calcium channel protein in brush border of intestinal cells) 1,25 dihydroxy vitamin D3 given at time 0 increases the expression of CaT1

  25. Changes in CaT1 mRNA levels with different amounts of D3

  26. Take Home Our best understanding is that calcium enters the duodenal cell through calcium channels which may contain a vitamin D responsive Ca-binding component. Entry is down an electrochemical gradient. Bonner, 1999 CaT1, a Ca channel protein in the brush border of human enterocyte, is regulated by 1,25-dihydroxyvitamin D. The vitamin appears to mediate changes in CaT1-mRNA levels. CaT1, therefore, could be the primary gatekeeper regulating homeostatic modulation of intestinal calcium absorption efficiency.

  27. Vitamin D responsive Calcium Absorption Blood Lumen Calcium ATPase Enterocyte Calbindin ATP Ca2+ CAT1 ase Calcium ATPase antiporter Ca2+ Ca2+ Ca2+ ATP Ca2+ ase Mg2+ (Na+) Albumin Paracellular Ca2+ Ca bound to fiber, phytate, oxalate, fatty acids CAT1 is a Ca2+ channel protein located in the brush border of mucosal cells Calbindin is a small (9 kD) protein in the cytosol of mucosal cells

  28. Unanswered Questions 1. Where exactly is CaT1 located and does raising CaT1 protein require it relocation to the absorbing membrane? 2. Is there any evidence for CaT1 location in mobile vesicles? 3. Does 1,25-dihydroxy vitamin D3 affect efflux of Ca2+ at the basolateral surface? 4. Does CaT1 also recognize Mg2+?

  29. Phosphorus (phosphate)

  30. Phosphorous Phosphorous absorption utilizes a Na/phosphate cotransporter (Npt2a) 1. Expressed in the brush border membrane 2. Saturable, carrier mediated and responsive to Vit D. 3. non-regulated diffusion may be the major absorption pathway with higher intake Duodenum, Jejunum Saturable, carrier-mediated Npt2a PO4= PO4= Na+ PO4= (Ca2+, Mg2+) Complexed with other minerals or as organic phosphate Vitamin D stimulated Enterocyte

  31. Human Study Fed Fractional Absorption 7 mg 65-75% 36 mg 11-14% Magnesium 1. Absorption depends on concentration 2. Absorption is saturable and non-saturable (7-10%) 3. Fully saturable in ileum but not jejunum (contrast with calcium) 4. Absorption in the colon significant 5. Vitamin D has no influence on magnesium absorption

  32. ATP ase Magnesium Cation channel protein (transient receptor protein TRP) Distal jejunum and ileum TRPM6 ATP Mg2+ Mg2+ Mg2+ ADP Mg2+ -bound to phytate, fiber, fatty acids Since TRPM6 operates by diffusion without co-transporters, Mg2+ absorption efficiency depends on the amount of Mg2+ in the diet and within the cell Enterocyte

  33. Microminerals 3d metals: Fe, Zn, Cu

  34. Microminerals Fe2+, Cu2+, Mn2+, Zn2+ Because of their very low cellular concentrations, the micronutrients rely on specific high affinity transporters and binding proteins for movement. Some collect in vesicles and use the vesicle as the transport factor. Redox-sensitive metals (Fe2+/Fe3+, Cu+/Cu2+) rely on valence state changes to be sequestered or transported from the cell.

  35. Metals such as Fe3+ and Zn2+ are more soluble in acid solutions due to a shift in the equilibrium towards the free ion Fe3+(aq) + 3OH-(aq) Fe(OH)3(s) Pulls equilibria H+ Zn(OH)2(s) Zn2+(aq) + 2OH-(aq) Solubility Fe(OH)3 solubility Zn(OH)2 solubility 2.0 3.0 4.0 5.0 6.0 7.0 8.0 9.0 1.0 pH

  36. Elements of Micromineral Absorption • Insolubility or iron and zinc is partially overcome by mucins secreted from the cells • Only Fe3+ and Cu+ can engage their respective transporters • Cytosolic sequestering and regulatory factors have the potential to lock the mineral within the cell and block its release • Internal movement of Zn2+, Cu+ and Fe3+ is primarily via vesicles • Basolateral surface release is redox sensitive for Fe and Cu • See Powell et al. The regulation of mineral absorption in the gastrointestinal tract. Proc. Nutr. Soc. 58(1), 147-153 (1999)

  37. Mucins Mucins are complex polysaccharides secreted into the lumen that assist in stabilizing the solubility of metal ions Mucins prevent alkaline-induced polymerization of category 2 metal ions and make the metal ion available to transporters on the enterocyte surface

  38. Correlation of spectra of Fe with iron absorption Importance of mucins in making “insoluble” iron available to membrane transporters Rudzki et al, 1973 Conrad et al, 1991 as cited in Powell et al, 1999

  39. Stomach (pyloric mucosa) Intestine (colon) Laminated mucous layer Mucous layer Mucosal goblet cells Pyloric mucosal cells

  40. Aluminum localization with the mucous layer at rat villi surfaces

  41. Events in the Cellular Absorption of Iron Heme Iron Non-heme iron Ferric (Fe3+) Iron Pathway Ferrous (Fe2+) Iron Pathway

  42. Three Pathways in Iron Absorption Fe2+ Pathway Divalent cation transporter (DCT-1, DCM-1,Nramp2) Fe3+ Pathway Mobilferrin-integrin Heme Pathway Heme carrier protein Dctyb reductase Fe3+ Fe2+ DCT1 gastroferrin integrin Mobilferrin-Fe3+ Mobilferrin Fe2+ Porphyrin ring Ferroportin 1 Hephaestin Cu Cu Cu

  43. B2-microglobulin Fe2+ Transferrin Iron Absorption (heme and non-heme) Duodenal Lumen Duodenal Mucosa Plasma Heme- Protein Heme + Polypeptides Biliverdin Bilirubin Bilirubin HFE CO CO Heme Oxygenase Heme Ferroportin Fe2+ Fe3+ Ferritin Dcytb reductase paraferrin Hephaestin Fe3+ FR DCT-1 Fe2+ Fe3+ Fe3+ Fe3+ Mobilferrin (vesicles) Fe3+ Fe3+ B3 integrin Mucin (gastroferrin)

  44. Nramp2 (Natural resistance associated macrophage protein) Nramp2 Nramp1 (no iron transport) Nramp2 (DMT1/DCT1) Transport Mn2+,Fe2+, Ni2+ DMT1 isoform 1 DMT1 isoform 2

  45. FeR DCT1 Mobilferrin Soluble mucins (gastroferrin) Fe3+ reductase Integrin anchor Secretions into the lumin (soluble mucins) retard hydrolysis of Cu, Fe and Zn permitting binding to transporters and more efficient uptake. Efficiency of transport is related to valance state with M+ > M2+ > M3+ Redox-active factors reduce Fe3+ to Fe2+ Divalent cation transporter (DCT1) transports M2+ metals (Fe2+, Ca2+,Cu2+, Zn2+), keeping out toxic metals such as Al3+. A former name of DCT1 is Nramp2. Mobileferrin on the inner side of the apical membrane receives metal from DCT1 and transfers it to cytosol.

  46. Mobilferrin HFE (human leukocyte antigen H) Ferritin (or paraferritin) or Fe 2-microglobulin (for Zn) HFE may be involved in stabilizing the above complexes to mobiltransferrin

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