L49 – Metabolic features of cardiac tissue Flashcards Preview

MBBS I CPRS > L49 – Metabolic features of cardiac tissue > Flashcards

Flashcards in L49 – Metabolic features of cardiac tissue Deck (54):
1

What is used for 60-70% Myocardial ATP production under normal aerobic conditions?

Non-esterified fatty acids (NEFA)

2

2 sources of Non-esterified fatty acids (NEFA)?

Diet (fatty acids, glucose)

Mobilize stored forms (triacylglycerides in
adipocytes, glycogen in liver and muscle)

3

How does dietary lipid reach myocardia? Start with dietary lipid in micelles

Dietary lipid (triglycerides (TG)) >
micelles > in small intestine (duodenum):
pancreatic lipase cleaves TG into fatty acids (FA) + glycerol > enter intestinal cell>
reconstitute 2-monoglycerides + FA into TG > coat with phospholipids / lipoprotein > chylomicrons enter blood via
lymphatics > heart

4

How does stored glycogen in liver become mobilized?

In liver: glucose > glycerol-3-phosphate + FA-CoA > TG > coat with lipoprotein to form VLDL > blood

5

How does stored TAG in adipose tissue become mobilized?

Hormone (e.g. glucagon) activate G protein > adenylate cyclas > cAMP > Protein Kinase A > activate lipase > TG becomes DAG > release FA + glycerol

6

What 2 ways is FA + glycerol released into blood?

1. Lipoprotein
2. Albumin

7

How does circulating TG enter skeletal/ cardiac muscle?

1. breakdown TG into FA + glycerol
2. FA enter muscle through FA translocase

8

fatty acid translocase (FAT)/CD36 has a preference for which type of Fatty acid?

Long chain fatty acid (LCFA)

9

What are the 2 enzymes on outer mitochondrial membrane for FA transport?

Acyl-CoA synthase

Carnitine palmitoyl-transferase 1 (CPT1)

10

Write the reaction catalysed by acyl-CoA synthase.

Fatty acid binding protein (FABP) + CoA + ATP > FABP + fatty acyl-CoA + AMP + PPi

11

Where does the reaction catalysed by acyl-CoA synthase occur?

Outside of outer mitochondrial membrane

12

Fatty acyl CoA enters intermembrane space of mitochondria. What is the reaction there?

fatty acyl- CoA + carnitine > fatty acylcarnitine + CoA

Catalyzed by Carnitine Palmitoyl-transferase 1 (CPT1)

13

Which enzyme is important in regulating whether FA can enter intermembrane space?

Carnitine Palmitoyl-transferase 1 (CPT1)

14

What is the role of Carnitine?

Carnitine takes over CoA in carrying FA from intermembrane space through inner membrane to mitochondrial matrix

15

Which two enzymes are found on inner mitochondrial membrane for FA transport?

Carnitine acylcarnitine translocase

Carnitine Palmitoyl-transferase II (CPT2)

16

What is the reaction of Carnitine Palmitoyl-transferase II (CPT2)? Where does it occur?

Fatty acylcartinine + CoA > fatty acyl CoA + cartinine

17

Where is fatty acyl CoA found in the membranes of mitchondria?

Outside mitochondria, in intermembrane space (before being converted to fatty acylcartinine and in matrix

18

Where is fatty acylcartinine found in the membranes of mitochondria?

In intermembrane space and matrix (before being converted to fatty acyl CoA)

19

What happens to the cartinine in matrix after being detached from fatty acylcartinine?

Carried by cartinine acylcartinine translocase from matrix to intermembrane space

20

What happens to fatty acyl CoA inside the matrix ?

undergoes β-oxidation to produce:

1. FADH2, NADH
2. Acetyl-CoA

21

What is the fate of the acetyl CoA made from the β-oxidation of fatty acyl CoA in mitochondria?

Acetyl-CoA (2-C) combines with
oxaloacetate to form citrate > enter TCA cycle > metabolized into
CO2, H2O, NADH, FADH2

22

What is the fate of the FADH2, NADH made from the β-oxidation of fatty acyl CoA in mitochondria?

Enter electron transport chain > pump H+
into intermembrane space > H+ goes down concentration gradient to drive ATP synthase > produce ATP

23

What accounts for the minority 30% of Myocardial ATP production under normal aerobic conditions?

Glucose

24

What is the fate of glucose used in ATP production in cardiomyocyte?

Enter cardiomyocyte via channel (e.g. GLUT 4) > glycolysis by hexokinase > form pyruvate

> pyruvate catalyzed by PDH to form Acetyl- CoA > TCA cycle > ETC > ATP made

25

What is the least used metabolite in Myocardial ATP production under normal aerobic conditions?

Lactate, ketone body

26

How is Fatty acid / glucose chosen for use in cardiomyocyte?

Reciprocally
Use one means inhibiting use of the other

27

When utilization of Fatty acid in mitochondria is high, what is the action of NADH made in B-oxidation?

NADH made in B-oxidation activates PDH KINASE > phosphorylate and inhibit PDH > pyruvate from glucose inhibited to form acetyl CoA

28

When utilization of Fatty acid in mitochondria is high, what is the action of citrate made in TAC cycle after B-oxidation?

Citrate leaves mitochondria by SLC25A1 channel > inhibits phosphofructokinase 1 in cytosol

(PFK1 = rate-limiting enzyme in glycolysis)

29

Which two enzymes are inhibited when FA utilization is high in cardiomyocyte? Which enzyme is activated?

PFK1 - inhibit by citrate
PDH - inhibit by activated PDH kinase (by NADH)

MCD/Malonyl-CoA decarboxylase is activated

30

When glucose utilization is high, Which enzyme is stimulated?

PDH is stimulated (e.g. by L-carnitine)

31

What is the role of MCD/Malonyl-CoA decarboxylase?

Transport LCFA into mitochondria when FA utilization is high

32

When glucose utilization is high, which enzyme is inhibited to stop FA oxidation?

Glucose > pyruvate > Acetyl CoA

Acetyl CoA A inhibits 3-ketoacyl thiolase (= last step in B-oxidation)

33

What are the 2 sources of Acetyl-CoA in cytosol when glucose utilization is high in cardiomyocyte?

1) Citrate leave mitochondria through SLC25A1 transporter > cleaved by ATP-citrate lyase (ACL) into acetyl CoA

2) Acetyl CoA in mitochondria > mitochondrial ACT > acetylcarnitine > cytosolic ACT > acetyl CoA

34

When glucose utilization is high, what enzyme is used to turn Acetyl CoA into malonyl CoA?

ACC
acetyl CoA carboxylase

35

What is the role of malonyl CoA in the heart when glucose utilization is high?

In heart > inhibit Carnitine palmitoyl-transferase 1 (CPT1) @ outer mitochondrial membrane > less FA enter mitochondria

36

What is the role of malonyl CoA in the liver when glucose utilization is high?

In liver: malonyl CoA > FA synthase > palmitate > FACoA

37

What is the enzyme for converting malonyl CoA back into Acetyl CoA?

malonyl CoA decarboxylase (MCD)

38

If O2 is in short supply, which metabolism pathway is stimulated and which is inhibited?

stimulate acetyl-CoA from glycolysis and inhibit β-oxidation

39

During oxygen deprivation, which metabolites accumulate? What metabolism is inhibited?

B-oxidation is inhibited > accumulate fatty acyl CoA, fatty acylcarnitine

Accumulation of acetyl CoA and NADH > inhibit PDH > stop glucose metabolism too

40

During Hypoxia / mild ischaemia, which pathway is stimulated to make ATP?

Accumulation of ADP, AMP stimulate PFK > glycolysis

Also trigger glycogenolysis

41

How does severe ischaemia cause cell death via ATP?

No O2 > accumulate lactate and H+ > inhibit PFK & glyceraldehyde 3-phosphate dehydrogenase > stop glycolysis > no ATP > irreversible cell injury and death

42

During aerobic reperfusion, what is generated that reacts with polyunsaturated membrane lipids (FA chains) to cause cellular injury?

Oxygen-derived free radicals

made from One-electron reduction of oxygen, electrons not taken up properly by antioxidants

43

What are the effects of oxygen derived free radicals to cause cellular injury?

Lipid peroxidation > degrade FA > increase membrane permeability > swelling

Damage mitochondria + mDNA
Damage DNA, SER, RER

44

Why does inhibition of FA oxidation excerbate the cellular injury caused by oxygen derived free radicals?

Stop B-oxidation > accumulate FA intermediates > inhibit glucose metabolism > uncouple ETC from oxidative metabolism

45

What free radicals are formed during aerobic reperfusion?

superoxide (O2-)
hydrogen peroxide (H2O2)
hydroxyl radical (OH')

46

Which metabolism pathway is better for ATP production after an episode of MI?

Glucose metabolism

Inhibit B-oxidation after episode of MI

47

What drugs are used to increase glucose utilization after an episode of MI?

Oxfenicine, (etomoxir, perhexiline)

T3 (triiodothyronine = thyroid hormone)\

glucose-insulin-potassium (G-I-K)

intralipid-heparin

MCD inhibitor

48

What is the function of Oxfenicine?

Increase glucose utilization, inhibit CPT1
Increase lactate and pyruvate production
Delay angina

49

What is the function of MCD inhibitor ?

Increase Malonyl CoA content > inhibit CPT1 > stop FA entering mitochondria

Stimulate PDH, thus glucose utilization

50

What is the function of T3?

improve coupling of glycolysis to glucose
oxidation

51

What is the function of glucose-insulin-potassium (G-I-K)?

help transport glucose into cell

52

What is the function of Infuse intralipid-heparin?

Displace LPL from heparan sulfate peptidoglycan (HSPG) on endothelial surface

> FA held by albumin but cannot enter tissues

53

What drug used to treat hypertension has a similar action to Oxfenicine and MCD inhibitor?

B-blockers inhibit CTP1 and 2 on mitochondria membranes

54

What drug directly inhibits B-oxidation?

Trimetazidine, ranolazine

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