integration of metabolism

coordination between different metabolic pathways inside the body is called integration of metabolism. this presentation discuss about how metabolism can be regulated and integrated in liver, muscle and adipose tissue.

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

4. compartmentalization 4

5. Key junction points Glucose 6-phosphate Pyruvate Acetyl CoA 5

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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

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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

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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

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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

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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

31. Brain in fasting 31

32. Kidney in long term fasting Gluconeogenesis Compensation for the acidosis 32

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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, 6 th edition, 2014 David L.Nelson , Michael M.Cox , lehninger principles of biochemistry, 6 th edition, 2013 Jererny M.Berg , John L.Tymoczko , Lubert Stryer , Biochemistry, 7 th edition, 2013 35

36. Thank you 36