integration of metabolism
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The integration of metabolism ensures a constant supply of fuel to all tissues. Metabolic pathways are controlled through four mechanisms: substrate availability, allosteric effectors, covalent modification of enzymes, and regulation of enzyme synthesis. During the absorptive state after a meal, elevated insulin and substrate availability promote anabolism through increased storage of carbohydrates, fats, and proteins in liver, adipose tissue, and skeletal muscle. In the fasting state, glucagon stimulates glycogenolysis, gluconeogenesis, and ketogenesis in the liver to maintain blood glucose levels while fatty acids are oxidized in other tissues.
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integration of metabolism
- 1. Integration of metabolism Mohammad Reza Abdullahi Master of medical science student in biochemistry IIUM, Malyasia 1
- 2. Overview • Coordination between different metabolic pathways inside the body is called integration of metabolism • It ensures a supply of suitable fuel for all tissues, at all the time (from fully fed state to the totally starved state) 2
- 3. Major metabolic pathway • Glycolysis • Gluconeogenesis • Glycogen metabolism • Fatty acid metabolism • Citric acid cycle • Amino acid metabolism • Oxidative phosphorylation 3
- 5. Key junction points • Glucose 6-phosphate • Pyruvate • Acetyl CoA 5
- 6. 6
- 7. Metabolic functions of the organs 7
- 8. Major organs involve in integration of fuel metabolism 8
- 9. Important hormones in metabolic pathway • Insulin • Glucagon 9
- 10. Insulin • Promote fuel storage • Synthesized by pancreatic β-cell (51 AA) • Released in response to carbohydrate ingestion • By dephosphorylation, activate energy storing enzymes • Increase enzyme synthesis (e.g. glucokinase) • Increase glucose uptake by muscle and adipose tissue 10
- 11. Metabolic effects of insulin • Effects on carbohydrate metabolism • Promote its storage • Increase glycogen synthesis in liver and muscle • Increase glucose uptake in muscle and adipose tissue • Effects on lipid metabolism • Inhibition of HSL activity • Increase metabolism of glucose in adipose tissue and gen expression of LPL • Effects on protein synthesis • Stimulate the entry of amino acids into cells and protein synthesis 11
- 12. 12
- 13. Glucagon • Promote glycogenolysis and gluconeogenesis in liver • Synthesized by pancreatic α-cells (29 AA) • Released in response to low plasma glucose level • By phosphorylation, activate some enzymes such as glycogen phosphorylase and hormone sensitive lipase • Induces gen expression of phosphoenolpyruvate carboxy kinase 13
- 14. Metabolic effects of glucagon • Effects on carbohydrate metabolism • Increase breakdown of liver glycogen • Increase gluconeogenesis • Effect on lipid metabolism • Inhibition of fatty acid synthesis • Activate hormone sensitive lipase • Effects on protein metabolism • Increase uptake of amino acids by liver 14
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- 16. Key points about hormonal influences on metabolism • Insulin and glucagon are the key hormones in the short-term regulation of blood glucose concentration under normal physiologic conditions. • Insulin has hypoglycemic effect while glucagon has hyperglycemic effect • Insulin primarily dephosphorylates enzymes, whereas glucagon primarily phosphorylates them 16
- 17. Absorptive state • 2-4 hours after meal • Increase glucose, amino acids and TG in plasma • Elevated insulin to glucagon ratio • Anabolic period 17
- 18. Enzymic changes in the absorptive state • Availability of substrates • Allosteric effector • Allosteric changes usually involve rate-determining reactions • e.g. glycolysis in the liver is stimulated following a meal by an increase in fructose 2,6-bis phosphate, an allosteric activator of phosphofructokinase-1 • Covalent modification • addition or removal of phosphate groups • Most of covalently regulated enzymes are active in dephosphorylated form • Induction and repression of enzyme synthesis • Insulin induces expression of acetyl coenzyme A carboxylase and fatty acid synthase • glucagon induces expression of phosphoenolpyruvate carboxykinase of gluconeogenesis 18
- 19. Liver Carbohydrate metabolism • Glucose enter in liver cells by GLUT-2 • Increase phosphorylation of glucose • Increase glycogenesis • Increase activity of PPP • Increase glycolysis • Decrease production of glucose 19
- 20. Fat metabolism • Increase fatty acid synthesis • Increase TG synthesis • Increase amino acids synthesis • Increase amino acids degradation Amino acids metabolism 20
- 21. 21
- 22. Adipose tissue • Carbohydrate metabolism • Increase glucose transport • Increase glycolysis • Increase activity of Pentose Phosphate Pathway • Fat metabolism • Increase TG storage 22
- 23. Resting skeletal muscle • Carbohydrate metabolism • Increase glucose transport • Increase glycogen synthesis • Fat metabolism • LPL release FA from VLDL and chylomicron • Protein metabolism • Increase protein synthesis • Increase uptake of branched-chain amino acids 23
- 24. Brain • Glucose as a fuel • GLUT-1 24
- 25. 25
- 26. Fasting state • Begin if no food is ingested after absorptive period • Plasma level of nutrients decrease • Decrease insulin/counterregulatory hormone ratio • Enzymatic changes 26
- 27. Liver in fasting • Carbohydrate metabolism • Increase glycogen degradation • Increase glucose synthesis • Lipid metabolism • Increase fatty acid oxidation • Increase ketone body synthesis • Protein metabolism 27
- 28. 28
- 29. Adipose tissue in fasting • Carbohydrate metabolism • Fat metabolism • Increase degradation of fat • Decrease uptake of fatty acid 29
- 30. Resting skeletal muscle in fasting • Carbohydrate metabolism • Lipid metabolism • Protein metabolism 30
- 32. Kidney in long term fasting • Gluconeogenesis • Compensation for the acidosis 32
- 33. 33
- 34. Summary • Integration of metabolism ensures a supply of suitable fuel for all tissues, at all the time • The flow of intermediates through metabolic pathways is controlled by four mechanisms • The elevated insulin-to-glucagon ratio and the ready availability of circulating substrates make the absorptive state an anabolic period • In fast state, fatty acids are oxidized in preference to glucose, to spare glucose for those tissue that require it (Brain & RBCs) • In fast state, glycogenolysis, gluconeogenesis and ketogenesis occur 34
- 35. References • Denise R.Ferrier, Lippincott’s illustrated review Biochemistry, 6th edition, 2014 • David L.Nelson, Michael M.Cox, lehninger principles of biochemistry, 6th edition, 2013 • Jererny M.Berg, John L.Tymoczko, Lubert Stryer, Biochemistry, 7th edition, 2013 35
- 36. Thank you 36
Editor's Notes
- Excess energy intake is stored as either glycogen or fat Under negative caloric balance fatty acids are oxidized in preference to glucose, to spare glucose for those tissues (brain and RBCs) that require it under all conditions.
- In general the main key junction points between metabolic pathways are intermediates: g6p, pyruvate and Acetyl CoA
- catecholamines epinephrine and norepinephrine
- Inhibition of fatty acid synthesis by inhibition of ACC. Glucagon increases uptake of amino acids by the liver that supplied by muscle, resulting in increased availability of carbon skeletons for gluconeogenesis
- The elevated insulin-to-glucagon ratio and the ready availability of circulating substrates make the absorptive state an anabolic period characterized by increased synthesis of TAG and glycogen to replenish fuel stores and enhanced synthesis of protein
- In contrast, gluconeogenesis is inhibited by fructose 2,6-bisphosphate, an allosteric inhibitor of fructose 1,6-bis phosphatase Three exceptions are glycogen phosphorylase kinase, glycogen phosphorylase and hormone-sensitive lipase of adipose tissue, which are inactive in their dephosphorylated form. By affecting transcription factor in cause induction and repression of enzyme
- Low affinity to glucose, increase glucose metabolism
- the flow of intermediates through the pathways of energy metabolism is controlled by four mechanisms: 1) the availability of substrates, 2) allosteric regulation of enzymes, 3) covalent modification of enzymes, and 4) induction–repression of enzyme synthesis
- The liver first uses glycogen degradation and then gluconeogenesis to maintain blood glucose levels Extremely active muscles use glycogen as their energy source, generating lactate via glycolysis. During recovery, some of this lactate is transported to the liver and converted to glucose via gluconeogenesis. This glucose is released to the blood and returned to the muscles to replenish their glycogen stores. The overall pathway (glucose S lactate S glucose) constitutes the Cori cycle.