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Section 10

Section 10. 8. Distribution of absorbed nutrients. 1/10/06. Digestive disorders. other topics: sweeteners GI hormone summary. aka malabsorption disorders condition nutrient molecular problem lactose intol. lactose ¯ lactase pern. anemia vitamin B 12 ¯ intrinsic factor

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Section 10

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  1. Section 10 8. Distribution of absorbed nutrients 1/10/06

  2. Digestive disorders other topics:sweeteners GI hormone summary aka malabsorption disorders condition nutrient molecular problem lactose intol. lactose ¯ lactase pern. anemia vitamin B12¯intrinsic factor celiac disease gluten* peptide antigenicity gallstones cholesterol crystal formation Hartnup neutral aa's ¯ Na+ aa symport disease * protein in wheat, barley, rye see Harper'sBiochem23 ed: p 620 1

  3. Obesity therapy: lipase inhibition • obesity: causative factor of cardiovascular disease, type II diabetes, cancer • pancreatic lipase a serine esterase (cf. trypsin, etc.: serine proteases) • Xenical (Orlistat) inactivates lipase • contains a reactive ester in a strained-ring moiety* (4-atom ring, a β-lactone) • reacts with active site serine residue of lipase 2 *penicillins contain similar reactive amide, a β-lactam

  4. Obesity therapy: lipase inhibition • obesity: causative factor of cardiovascular disease, type II diabetes, cancer • pancreatic lipase a serine esterase (cf. trypsin, etc.: serine proteases) • Xenical (Orlistat) inactivates lipase • contains a reactive ester in a strained-ring moiety* (4-atom ring, a β-lactone) • reacts with active site serine residue of lipase • does not inhibit systemic lipases: e.g., adipocyte lipase, lipoprotein lipase in capillaries (slide 14) • recommended therapy: dose producing ~30% decrease in fat absorption 2 *penicillins contain similar reactive amide, a β-lactam

  5. Overview-review nutrients digestion, absorption glucose, amino acids, fats distribution precursors, available fuels metabolism macromolecules, energy, end products 1

  6. Distribution of absorbed nutrients • alternating statesabsorptive (feeding) postabsorptive (fasting) • absorptive statehyperglycemia, hyperlipemia, hyperaminoacidemia 3

  7. Distribution of absorbed nutrients • alternating statesabsorptive (feeding) postabsorptive (fasting) • absorptive statehyperglycemia, hyperlipemia, hyperaminoacidemia • events or functions during absorptive state • supply fuel for immediate need • replenish proteins • restore glycogen consumed • storage of excess nutrients as fat 3

  8. 1 2 Liver: fate of monosaccharides glc, fructose, galactose, mannose, etc glc-6P glycogen glc derivatives: glucuronate glucosamineetc 4

  9. 1 2 3 Liver: fate of monosaccharides glc, fructose, galactose, mannose, etc glc-6P glycogenglc derivatives:acetyl CoA glucuronateNADPH, etc glucosamineetcfatty acids TG (to adipocytes via lipoproteins: VLDL) excess 4

  10. 1 2 Liver: fate of amino acids amino acids synthesis: synthesis: liver & other aa plasma choline proteins bile salts creatine etc 5

  11. 1 2 3 Liver: fate of amino acids amino acids synthesis: synthesis: pyruvate, Krebs cycle liver & other aa intermediates plasma choline proteins bile salts acetyl CoA, fats, glc creatineetc excess 5

  12. 1 2 Liver: fate of triglycerides (TGs, TAGs) & VLDL remnants^ triglycerides (via chylomicron remnants) glycerol + FA glucose acetyl CoA steroids: cholesterol, bile salts, etc fuel 6

  13. 1 2 3 Liver: fate of triglycerides (TGs, TAGs) & VLDL remnants^ triglycerides (via chylomicron remnants) apolipoproteins glycerol + FA phospholipids glucose acetyl CoA steroids: plasma cholesterol, lipoproteins bile salts, etc(to adipose, other tissues) excess fuel 6

  14. Major plasma lipoproteins: composition Average percent composition lipoprotein protein phospho- chol chol triglyc- class lipids esters erides chylomicron 2 8 2 4 84 chylomicronremnant 6 24 6 12 52 very low densitylipoprotein (VLDL) 5 15 7 13 60 low densitylipoprotein (LDL) 20 20 10 30 20 high densitylipoprotein (HDL) 50 30 4 12 4 7

  15. Major Plasma Lipoproteins sters chylomicron chylomicronremnant very low densitylipoprotein (VLDL) low densitylipoprotein (LDL) high densitylipoprotein (HDL) 8

  16. Major plasma lipoproteins: function lipoprotein class main transport functionchylomicron lipids: intestine → liver, adipose very low density TG: liver → adipose, others lipoprotein (VLDL) low density chol: liver → peripheral tissues lipoprotein (LDL) high density chol: peripheral tissues → liver lipoprotein (HDL) 9

  17. Transport by lipoproteins Lehninger et al., 3rd ed., Fig. 21-38 gif 150% 10

  18. Plasma lipoprotein structure Stryer 4edFig. 27-20 Fig. 26-16 • nonpolar lipid core covered by a shell of amphiphilic PL & protein • protein has surface with information controlling binding, exit & entry ofparticles at specific target cells • on LDL, it is apolipoprotein B–100that binds to LDL receptor proteinon target cell surface • cf. chylomicron: lect. 7, sl 16 cf. Lehninger et al., 3rd ed., Fig. 21-37 cholesterol phospholipid cholesteryl ester apolipoprotein B-100 11

  19. Packaging for transport Lehninger et al., 3rd ed., Fig. 17-2 apolipo-proteins Lehninger et al., 2nd ed., Fig. 16-2 chylomicrons • particles for transport of lipids to liver & adipocytes • size: 0.1–1 µm • average composition: TG (84%) chol (2%) cholE (4%) PL (8%) apolipoproteins (2%) PL chol PL 16 cholE, TG

  20. LDL & its receptor (cf. S7L4sl13) cholesterol: • transported to peripheral cells via LDL • used for cell membrane synthesis or stored as esters • represses transcription of LDL receptor gene LDLreceptors (membranesynthesis) cholesteryllinoleate cholesterol cholesteryloleate(storage) protein LDL amino acids Adapted fromFig. 12-40 ↓receptor synthesis binding →endocytosis→ lysosomalhydrolysis regulatoryactions: → 12

  21. Fate of nutrients: other cells • glucose uptake by facilitated diffusion • most cells: GLUT1 & GLUT3 • muscle & adipose: GLUT4 • insulin stimulates movement of vesicles containing GLUT4 to plasma membrane (S9L2sl19) • adipose: glucose supplies precursors for synthesis of triglycerides • glycerol P • e–s (NADPH) • acetyl CoA • amino acid uptake by facilitated diffusion • muscle: insulin required (transport proteins analogous to GLUT4) 13

  22. insulin binding activates exocytosis Insulin & GLUT4 • at high [glc],facilitated diffusionmediated by GLUT4(muscle & adipose) • similar mechanismoperates fortransport of amino acidsinto muscle GLUT4(glucosetransporter) GLUT4 “stored”in vesicles as [insulin]¯, endocytosis removes GLUT4 budding fusion endo-some produce intracellularinsulin effects Lehninger et al.,3rd ed., p. 414 19

  23. Fate of nutrients: other cells • dietary triglycerides & cholesterol VLDL,chylomicron TGchol TG glucose↓glycerol-P LIPOPROTEINLIPASE FA FA capillary lumen↑ by insulin glycerol VLDL,chylomicronremnants TGchol fuel adipocytes, others receptor FA, cholesterol liver 14

  24. Postabsorptive (fasting) state • starts when hyperglycemia, hyperlipemia & hyperaminoacidemia are over Fuels available (70-kg person) fuelkg kcal glycogen 0.4 1600 protein 6 24,000 triglycerides 15 135,000 total 161,000 • despite the abundance of fat, the other more versatile and scarcer fuels are also consumed during fasting Fuel versatility amino acids↓↑* ↓ glucose→ fatty acids *C-skeletons of nonessential amino acids 15

  25. Fasting: control of fuel use short-term • most cells mainly use fatty acids & ketone bodies • source lipolysis in adipocytes stimulated by glucagon & epinephrine • brain major exception; requires glucose • sources liver glycogen (~60 g/day) protein (~75 g/day) stimulated by glucagon (liver) & cortisol (muscle) 16

  26. Fasting: control of fuel use • liver main fuel processor converts • glycerol, lactate & amino acids via gluconeogenesis to glucose • fatty acids to ketone bodies long-term fasting • after many days, brain adapts to using ketone bodies (kb) induction of – proteins for kb uptake– enzymes for kb metabolism eventually kb supply ~½ brain's energy needs • result: protein consumption decreases from ~75 g/day to ~20 g/day 17

  27. Distribution of absorbed nutrients • alternating statesabsorptive (feeding) postabsorptive (fasting) • absorptive statehyperglycemia, hyperlipemia, hyperaminoacidemia • events or functions during absorptive state • supply fuel for immediate need • replenish proteins • restore glycogen consumed • storage of excess nutrients as fat 18

  28. Next :4. Major nutrients

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