PETER PAZMANY CATHOLIC UNIVERSITY Consortium members SEMMELWEIS UNIVERSITY, DIALOG CAMPUS PUBLISHER

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SEMMELWEIS UNIVERSITY PETER PAZMANY CATHOLIC UNIVERSITY Development of Complex

framework** Consortium leader PETER PAZMANY CATHOLIC UNIVERSITY Consortium members

the support of the European Union and has been co-financed by the European Social

fejlesztése konzorciumi keretben ***A projekt az Európai Unió támogatásával, az

1 SEMMELWEIS UNIVERSITY PETER PAZMANY CATHOLIC UNIVERSITY Development of Complex Curricula for Molecular Bionics and Infobionics Programs within a consortial* framework** Consortium leader PETER PAZMANY CATHOLIC UNIVERSITY Consortium members SEMMELWEIS UNIVERSITY, DIALOG CAMPUS PUBLISHER The Project has been realised with the support of the European Union and has been co-financed by the European Social Fund *** **Molekuláris bionika és Infobionika Szakok tananyagának komplex fejlesztése konzorciumi keretben ***A projekt az Európai Unió támogatásával, az Európai Szociális Alap társfinanszírozásával valósul meg TÁMOP /2/A/KMR

2 Semmelweis University ORGANIC AND BIOCHEMISTRY (Szerves és biokémia) Biochemical interpretation of biological phenomena (Biológiai jelenségek biokémiai értelmezése) Krasimir Kolev TÁMOP /2/A/KMR

3 Lecture objectives At the end of the presentation the participant will be able: 1) To discuss the metabolic background of atherosclerosis 2) To interpret the dietary and pharmacological tools to prevent the progress of atherosclerosis 3) To understand the molecular background of fuel utilization in the course of exercise 4) To understand the metabolic factors of fatigue TÁMOP /2/A/KMR

4 Part 1: Atherosclerosis DEF : the price of conserving cholesterol? TÁMOP /2/A/KMR

5 Mortality statistics of WHO 2004 (percentage of total death events) Death cause World Europe America West Pacific SE Asia Eastern Mediterranean Africa Cardioand cerebrovascular 29,3 51,5 (59,9) 32,3 32,0 26,7 26,0 9,7 Infection 26,0 5,1 4,4 18,4 29,9 31,3 63,1 Tumor 12,5 19,2 18,7 19,4 7,9 6,6 3, TÁMOP /2/A/KMR

6 Morphological background of ischemic heart attack Blood clot formed on the surface of atherosclerotic plaque blocks the blood flow to the tissue causing acute tissue damage TÁMOP /2/A/KMR

7 Macroscopic view of atherosclerotic plaque 1. Internal surface of right coronary artery from a 32-year-old man. The atherosclerotic plaque is yellowish in the central region TÁMOP /2/A/KMR

8 Macroscopic view of atherosclerotic plaque 2. A cross-section of coronary artery that has significant luminal obstruction by an atherosclerotic plaque with a lipidrich core TÁMOP /2/A/KMR

9 Microscopic view of atherosclerotic plaque The region indicated by arrows and stained in pink represents the lipidrich atherosclerotic plaque TÁMOP /2/A/KMR

10 Overview of the molecular events in the course of formation of atherosclerotic plaque TÁMOP /2/A/KMR

Initiation of atherosclerotic plaque formation 1.

11 Initiation of atherosclerotic plaque formation TÁMOP /2/A/KMR

12 Initiation of atherosclerotic plaque formation 2. DEF TÁMOP /2/A/KMR

13 Sources of reactive oxygen species TÁMOP /2/A/KMR

14 Foam cell DEF formation TÁMOP /2/A/KMR

15 Elevation of triglyceride level (TG in VLDL and chylomicrons) accelerates the exchange of TG for CE between lipoproteins. The TG-rich HDL and LDL are better substrates of hepatic lipase resulting in small and dense (sd) particles. The sdhdl loses its ApoA1, which is released in the kidneys. The sdldl is a poor ligand of LDLreceptor, circulates longer in blood with higher probability for oxidation (more uptake through SR). Hypertriglyceridemia and atherosclerosis TÁMOP /2/A/KMR

16 Summary of the atherogenic effects of plasma triglycerides TÁMOP /2/A/KMR

17 Pharmacological tools to reduce blood LDL levels: inhibitors of HMG-CoA reductase (statins) TÁMOP /2/A/KMR

18 Structure of statins Statins are structural analogs of the product of HMG-CoA reductase and thus bind the active site and inhibit the enzyme TÁMOP /2/A/KMR

19 Pharmacological tools to reduce blood LDL levels: bile acid binding resins (cholestyramine) TÁMOP /2/A/KMR

20 Pharmacological tools to reduce blood LDL levels: modulators of metabolite receptors (elixirs, FiXeRs) TÁMOP /2/A/KMR

Dietary tools to reduce blood LDL levels: unsaturated fatty acids (fish and plant oils) Low K M for unsaturated fatty acids more cholesteryl esters

21 Dietary tools to reduce blood LDL levels: unsaturated fatty acids (fish and plant oils) Low K M for unsaturated fatty acids more cholesteryl esters less free cholesterol in the membrane SREBP cleavage high level of LDL-receptor low plasma cholesterol TÁMOP /2/A/KMR

22 Effect of low cholesterol, high unsaturated fatty acid diet on the size of the plaque TÁMOP /2/A/KMR

23 Dietary tools to reduce blood LDL levels: ethanol (alcoholic drinks) The moderate consumers (1-3 drinks/day) have 20 % lower mortality risk than abstinent subjects because of lower prevalence of strokes and heart attacks TÁMOP /2/A/KMR

24 Effect of alcohol on the composition of plasma lipoproteins Alcohol opposes the atherogenic effect of triglycerides. It impairs the function of CETP and thus it prevents the formation of small and dense LDL and HDL. Mild genetic impairment of the CETP function is a longevity variance. The prevalence of the I405V CETP variant in homozygous form is 25 % in 270 subjects at the age of years in contrast to the 8 % in the general population TÁMOP /2/A/KMR

25 Dietary tools to reduce blood LDL levels: antioxidants (red wine, fruits) Vitamin E (tocopherol) ROO. + A-OH ROOH + A-O. Antioxidants decrease the probability of LDL oxidation in circulation TÁMOP /2/A/KMR

26 Major dietary sources of antioxidants hydroxybenzoate gallate catechin Antioxidant equivalent 1 glass(150 ml) red wine = 12 glasses white wine = 500 ml beer = 1000 ml orange juice = 3000 ml apple juice = 5 apples = 500 ml tea TÁMOP /2/A/KMR

27 Part 2: Metabolism of exercise TÁMOP /2/A/KMR

28 Molecular basics of muscle contraction The interaction of actin and myosin is triggered by Ca 2+ binding to troponin C. Following binding to actin, the myosin head changes conformation and the Z-disks slide closer to each other (contraction). The detachment of actin from myosin requires the replacement of ADP in myosin by ATP, following which the myosin head can take part in a new cycle of interaction with actin when ATP is hydrolyzed to ADP by the myosin ATP-ase activity TÁMOP /2/A/KMR

29 Sources of ATP in the course of muscle contraction (short term, anaerobic alactic phase in the range of seconds) 2ADP Adenylate kinase ATP+AMP creatine-p+adp Creatine kinase creatine+atp TÁMOP /2/A/KMR

30 Sources of ATP in the course of muscle contraction (intermediate term, anaerobic lactic phase in the range of minutes) TÁMOP /2/A/KMR

31 Formation and elimination of lactate in the muscle In the initial stages of exercise, before the adaptation of blood supply (up to several minutes) anaerobic glycolysis provides ATP with final metabolite lactate released in blood. The major source of glucose 6-phosphate under these conditions is muscle glycogen. The net yield of ATP per glucose 6- phosphate unit is TÁMOP /2/A/KMR

32 Regulators of lactate production in the initial stage of exercise 1. Ca 2+ : trigger of contraction and activator of glycogen phosphorylase kinase (through calmodulin binding) 2. AMP: generated by adenylate kinase and allostric activator of glycogen phosphorylase and fructose 6-phosphate kinase (1 and 2) 3. Discrepancy between the generation of NADH and pyruvate in the cytosol and the capacity of mitochondria to utilize them TÁMOP /2/A/KMR

33 Sources of ATP in the course of muscle contraction (long term, aerobic phase in the range of minutes and hours) TÁMOP /2/A/KMR

34 Regulators of fuel utilization in prolonged exercise The ADP generated by the myosin ATP-ase is converted in part to AMP which in turn activates the AMPK (Pi in the scheme on the right indicates phosphorylation of the target enzyme). The phosphorylation of ACC results in its inhibition and reduced levels of malonyl-coa. Thus, the transfer of long chain fatty acids to the matrix of mitochondria is accelerated with consequent increase in their β-oxidation TÁMOP /2/A/KMR

35 Key regulatory interrelations in fuel utilization in prolonged exercise TÁMOP /2/A/KMR

36 Effect of the feeding state and exercise on fatty acid utilization in muscle In the well-fed state the utilization of glucose suppresses the fatty acid oxidation (glucose line in the figure). Several hours after a meal (post absorptive line) fatty acid oxidation dominates (citrate effects on glycolysis). Light exercise further stimulates fatty acid utilization (AMP effects). Heavy exercise partially limits fatty acid oxidation (CoA trap in mitochondria) TÁMOP /2/A/KMR

37 Interpretation of exercise intensity and fatigue in terms of rate and capacity to produce ATP from different substrates Rate of ATP generation Capacity for ATP generation CHO: carbohydrate; FFA: free fatty acid; Data are given per kg dry weight of muscle tissue TÁMOP /2/A/KMR

38 Messages to take home 1) Atherosclerosis is an inflammatory disease of large arteries initiated by excessive deposition of cholesterol in cell of the blood vessel wall. 2) A major tool to prevent the progress of atherosclerosis is a diet poor in cholesterol and rich in unsaturated fatty acids, fibers and accompanied by moderate alcohol consumption 3) The pharmacological tools to treat excessive blood cholesterol levels target the absorption of cholesterol, the endogenous cholesterol synthesis and the disposal of excess cholesterol 4) Muscle glycogen is the first fuel that is utilized in the initial stage of exercise primarily in an anaerobic manner 5) The energy for sustained exercise is provided by the oxidation of fatty acids 6) The consumption of fuels limits the performance of the muscle in later stages of exercise resulting in fatigue TÁMOP /2/A/KMR

39 Comprehension problem 1. Which factor is necessary for the deposition of cholesterol in the atherosclerotic plaque? 1) LDL receptor 2) scavenger receptor 3) oxidation of LDL 4) reactive oxygen scavengers 5) alcohol A: 1,2 B: 2,3 C: 3,4 D: 3,5 E: 3, TÁMOP /2/A/KMR

40 Comprehension problem 2. Which factor is necessary for the formation of small and dense LDL? 1) CETP 2) hepatic lipase 3) high level of triglyceride in VLDL 4) HDL 5) alcohol A: 1 B: 1,2 C: 1,2,3 D: 1,2,3,4 E: all TÁMOP /2/A/KMR

41 Comprehension problem 3. Which statement is true considering the effects of alcoholic drinks? A: the higher the daily consumption of alcohol, the lower the mortality B: the alcohol increases the risk of atherosclerosis C: ethanol improves the action of CETP D: ethanol impairs the action of CETP E: ethanol lowers the level of triglyceride in blood TÁMOP /2/A/KMR

42 Comprehension problem 4. Which enzymes are under the direct regulation by AMP in skeletal muscle? 1) glycogen phosphorylase 2) carnitine palmitoyl acyltransferase I 3) phosphofructokinase 4) adenylate kinase 5) creatine kinase A: 1,2 B: 1,3 C: 2,4 D: 2,5 E: 4, TÁMOP /2/A/KMR

43 Comprehension problem 5. Which factors contribute to the increase in lactate release from working muscles (all comparisons refer to the base levels at rest)? 1) higher level of AMP 2) higher level of Ca 2+ 3) higher NADH/NAD ratio 4) lower level of malonyl-coa 5) lower acetyl-coa/coa ratio A: 1 B: 1,2 C: 1,2,3 D: 1,2,3,4 E: all TÁMOP /2/A/KMR

44 Comprehension problem 6. Which fuel is the basic source for ATP replenishment in prolonged (over an hour) exercise? A: creatine phosphate B: blood glucose C: muscle glycogen D: liver glycogen E: fatty acids TÁMOP /2/A/KMR

45 Recommended literature Orvosi Biokémia (Ed. Ádám Veronika): pp , Orvosi patobiokémia (Ed. Mandl, Machovich): pp TÁMOP /2/A/KMR

46 Answers to comprehension problems: 1. B; 2. C; 3. D; 4. B; 5. C; 6. E TÁMOP /2/A/KMR

PETER PAZMANY CATHOLIC UNIVERSITY Consortium members SEMMELWEIS UNIVERSITY, DIALOG CAMPUS PUBLISHER

PETER PAZMANY CATHOLIC UNIVERSITY SEMMELWEIS UNIVERSITY Development of Complex Curricula for Molecular Bionics and Infobionics Programs within a consortial* framework** Consortium leader PETER PAZMANY