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PHYSL 404 - Cardiovascular Physiology > 7 - Cardiac Metabolism > Flashcards

7 - Cardiac Metabolism Flashcards

1
Q

What is intermediary metabolism?

What are the 2 metabolic pathways?

A

The chemical reactions that occur in the cells of our bodies

  1. Catabolism
  2. Anabolism
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2
Q

Define catabolism

A

Metabolic pathways that breakdown molecules into smaller intermediates

  • Releases energy/ATP
  • eg oxidation
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3
Q

Define Anabolism

A

Metabolic pathways that construct larger intermediates from smaller molecules and consume energy

eg fatty acid biosynthesis

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4
Q

Why is intermediary energy metabolism so important in the heart?

A

on a per gram basis, the heart is the most metabolically demanding organ in the body

  • pumps 7200L of blood/day
  • accounts for ~10% of whole-body fuel consumption
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5
Q

Although the heart oxidizes virtually all substrates provided to it, its preference is for ________ and _______

A

Although the heart oxidizes virtually all substrates provided to it, its preference is for fatty acids and carbohydrates

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6
Q

_________ and ______ can provide anywhere from 5-10% of hearts oxidative metabolism?

A

ketone bodies and amino acids can provide anywhere from 5-10% of hearts oxidative metabolism?

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7
Q

_________ and ______ can provide anywhere from 5-10% of hearts oxidative metabolism?

A

ketone bodies and amino acids can provide anywhere from 5-10% of hearts oxidative metabolism?

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8
Q

When are carbohydrates the more important energy source for the heart?

A

Fatty acids are the primary fuel but during transition from fasting to feeding and secretion of insulin, carbohydrates become more important

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9
Q

The hearts metabolic state often depends on the ____________

A

The hearts metabolic state often depends on the c_irculating concentrations of substrates and hormones_

A healthy heart is flexible => can transition to different fuel sources

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10
Q

What happens regarding energy metabolism in the heart during fasting/starvation?

A
  • During starvation/fasting
    • Increased adipose tissue lipolysis
      • increases circulating fatty acid levels
        • circulating glucose and insulin (inhibit lipolysis) levels are low (from beta cells)
        • glucagon (activates lipolysis) levels are high (from alpha cells)
  • The transcription factor peroxisome proliferator activated receptor alpha (PPAR-alpha) is active
    • increases expression of fatty acid uptake and fatty acid oxidation enzymes
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11
Q

What is the key hormone that primes the heart to oxidize fatty acids during fasting?

A

Glucagon

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12
Q

What leads to increased lipolysis during fasting/starvation?

A
  • Low levels of insulin and glucose from pancreatic beta cells (which inhibit lipolysis)
  • High levels of glucagon from pancreatic alpha cells (activates lipolysis)
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13
Q

Which transcription factor in the heart is activated during starvation/fasting?

A

PPAR-alpha (Peroxisome proliferator activated receptor alpha)

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14
Q

What is the effect of PPAR-alpha (peroxisome proliferator activated receptor alpha)?

A

Increases expression of fatty acid uptake and fatty acid oxidation enzymes

RECALL: PPAR-alpha is active during fasting/starvation to facilitate transition to metabolizing fatty acids rather than carbohydrates

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15
Q

What happens regarding energy metabolism in the heart following nutrient ingestion (feeding)?

A
  • Following a meal, circulating carbohydrates are increased
    • leads to increased insulin secretion
      • insulin
        • inhibits adipose tissue lipolysis
        • stimulates glucose uptake and glucose metabolism in the heart
        • inhibits the transcription factor FoxO1 (which inhibits cells ability to metabolize carbs)
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16
Q

______ is the key hormone that primes the heart to oxidize carbohydrates during feeding

A

Insulin is the key hormone that primes the heart to oxidize carbohydrates during feeding

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17
Q

What leads to increased insulin secretion and decreased adipose tissue lipolysis following nutrient ingestion?

A
  • Insulin increased after feeding due to increased circulating carbohydrates
  • Insulin inhibits adipose tissue lipolysis
  • Insulin stimulates glucose uptake and metabolism
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18
Q

Which transcription factor in the heart is inhibited by insulin?

A

FoxO1 - inhibits cells ability to metabolize carbs

Insulin inhibits FoxO1 therefore activating cells ability to metabolize carbs

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19
Q

What are three additional hormones/circulating factors that influence cardiac metabolism?

A
  • Leptin/Adiponectin
  • Glucagon-like peptide-1
  • Tumor Necrosis Factor alpha
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20
Q

Effect of leptin/Adiponectin on cardiac metabolism

A

Leptin/Adiponectin are Adipokine hormones that increase fatty acid oxidation rates in the heart

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21
Q

Effect of glucagon-like Peptide-1 on cardiac metabolism

A

Glucagon-like Peptide-1 is a gut secreted hormone that influences insulin/glucagon secretion

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22
Q

Effect of Tumor Necrosis Factor alpha (TNF) on cardiac metabolism

A

TNF-alpha is an inflammatory cytokine that may impair fatty acid oxidation rates in the heart

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23
Q

Circulating concentrations of nutrients/substrate levels are critical determinants of ____________

A

Circulating concentrations of nutrients/substrate levels are critical determinants of myocardial energy metabolism

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24
Q

What is the principle of the Randle Cycle?

A

As the oxidation of either glucose or fatty acids is increased, it decreased oxidation of the other substrate

  • named after Philip Randle who first observed this in 1960s
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25
Which cardiac fuel source is more oxygen efficient?
Carbohydrates (glucose) are more oxygen efficient * Despite fatty acids producing more ATP/mol of substrate, they produce LESS ATP/mole Oxygen consumed versus glucose
26
What transporter(s) control(s) myocardial glucose uptake?
* GLUT4 * primary insulin-sensitive glucose transporter * GLUT1 * not insulin-sensitive * controls *basal glucose uptake*
27
The primary insulin-sensitive glucose transporter
GLUT4
28
Controls basal glucose uptake (no insulin sensitivity)
GLUT 1
29
Which GLUT transporter is ALWAYS present at the membrane?
GLUT-1 (controls basal glucose uptake)
30
\*\*\*\*\*\*\*ADD IMAGE FROM SLIDE 19\*\*\*\*\*\* How does GLUT-4 get relocated to the membrane?
Via Akt (PKB) * critical kinase controlling insulin's actions on glucose metabolism * Causes translocation of GLUT-4 transporters to membrane
31
What is glycogen?
A compact energy storage form comprised of multibranched chains of glucose
32
\_\_\_\_\_\_\_\_\_\_\_ is an intermediate in glycolysis and the **precursor for glycogen synthesis**
_Glucose-6-Phosphate (G6P)_ is an intermediate in glycolysis and the **precursor for glycogen synthesis**
33
(Glycogen synthesis) What is the energy investment required for each glucose molecule that is added to the glycogen backbone?
1 ATP/glucose molecule
34
(Glycogen synthesis) The Glucosyl group of ___________ is added to a growing glucose oligosaccharide chain via \_\_\_\_\_\_\_\_\_\_\_
The Glucosyl group of _uridine diphosphate glucose_ is added to a growing glucose oligosaccharide chain via _glycogen synthase_
35
(Glycogen Synthesis) What happens when the growing glucose oligosaccharide is at least \>11 residues?
The branching enzymes become involved
36
Condense the three points emphasized regarding myocardial glycogen synthesis:
* 1 atp/glucose molecule added to backbone * uridine diphosphate glucose added via glycogen synthase * branching enzymes become involved when glucose oligosaccharide chain is \>11 residues * adds branches to growing glycogen
37
(Myocardial Glycogen Breakdown) \_\_\_\_\_\_\_\_\_ is activated via increased AMP and inorganic phosphate levels and produces G6P for glycolysis
(Myocardial Glycogen Breakdown) is activated via increased AMP and inorganic phosphate levels and produces G6P for glycolysis
38
(Myocardial Glycogen Breakdown) When 4 glucose residues away from branch point, what becomes involved?
When 4 glucose residues from branch point, **debranching enzymes** (glycosyltransferase and alpha(1-6)glucosidase) become involved * Glycosyltransferase removes the terminal 3 residues to add onto an existing chain * alpha(1-6)glucosidase liberates the remaining residue as free glucose
39
(Myocardial Glycogen Breakdown) What happens to the free glucose liberated by alpha (1,6) glucosidase? Why is this important?
The free glucose is immediately phosphorylated by hexokinase and is used to produce energy via glycolysis (or glucose oxidation depending on metabolic demand) Important because the heart does not express glucose-6-phosphatase (enzyme that hydrolyzes glucose 6-phosphate resulting in creation of Pi and free glucose)
40
What are the three regulatory enzymes of glycolysis in the heart?
* Hexokinase * phosphorylates glucose to glucose-6-phosphate * Phosphoglucose Isomerase * converts glucose-6-phosphate to fructose-6-phosphate * Phosphoglycerate kinase * transfers phosphate from 1,3-bisphosphoglycerate to make 3-phosphoglycerate and ATP
41
What is the rate-limiting enzyme of glycolysis?
Phosphofructokinase (PFK) When energy levels are high (high ATP) PFK is allosterically inhibited (by atp) resulting in reduced glycolysis rates
42
Accumulation of glucose-6-phosphate inhibits _______ (enzyme)
Accumulation of glucose-6-phosphate inhibits _hexokinase_ (enzyme)
43
\_\_\_\_\_\_\_\_\_\_\_ stimulates pyruvate kinase activity
_Fructose-1,6-Biphosphate_ stimulates pyruvate kinase activity
44
PFK (Phosphofructokinase) is stimulated by \_\_\_\_\_\_\_\_
PFK (Phosphofructokinase) is stimulated by _high AMP levels during low energy states_
45
What is the net gain of ATP if glucose is the starting material?
2 ATP consumed (hexokinase and phosphofructokinase) 4 ATP produced Net gain 2 ATP
46
What is the net ATP gain if the glucose used in glycolysis originates from glycogen? Why is there this discrepancy?
Net gain of 3 atp because it bypasses the hexokinase step
47
Which two enzymes generate ATP in the absence of oxygen (anaerobic glycolysis?
Phosphoglycerate kinase Pyruvate kinase (Known as **substrate level phosphorylation** – take phosphate from glucose and add it to ADP)
48
In low oxygen conditions (ischemia) what happens to Pyruvate?
* Oxidative metabolism of pyruvate is inhibited * Instead of entering the mitochondria, LDH converts pyruvate to **Lactate** and recycles NADH into NAD+ LDH = Lactate Dehydrogenase
49
\*\*\*\*\*INSERT IMAGE FROM SLIDE 26\*\*\*\*\*\*\* ______ can become the rate-limiting enzyme for glycolysis during ischemia
_GAPDH_ (Glyceraldehyde 3-phosphate dehydrogenase) can become the rate-limiting enzyme for glycolysis during ischemia
50
is the rate limiting enzyme for glucose oxidation
_PDH (pyruvate dehydrogenase)_ is the rate limiting enzyme for glucose oxidation
51
What activates PDH (pyruvate dehydrogenase)?
PDH is activated when **dephosphorylated** by **PDH phosphatase (PDHP)**
52
What inactivates PDH?
PDH is inactivated via **phosphorylation** by **PDH kinase (PDHK)**
53
PDH is active when ________ and inactive when \_\_\_\_\_\_\_\_
PDH is active when _dephosphorylated_ and inactive when _phosphorylated_
54
What is FoxO?
Transcription factor activated during fasting and inhibited by insulin (via Akt) * FoxO - forkhead box protein 0
55
(REGULATION OF GLUCOSE OXIDATION IN THE HEART) PDHP (pyruvate dehydrogenase phosphatase) is activated by ________ and \_\_\_\_\_\_\_
PDHP (pyruvate dehydrogenase phosphatase) is activated by _Calcium (Ca++ eg from heavy exercise)_ and _insulin (primes heart to burn carbs)_ Recall: PDHP dephosphorylates PDH thus activating it (to convert pyruvate to acetyl coa)
56
(REGULATION OF GLUCOSE OXIDATION IN THE HEART) PDHK is inactivated by \_\_\_\_\_\_\_
PDHK is inactivated by _high pyruvate levels_ (feed forward inhibition) Recall: PDHK = pyruvate dehydrogenase kinase PDHK phosphorylates PDH to inactivate PDH Therefore, inactivating PDHK will activate PDH
57
(REGULATION OF GLUCOSE OXIDATION IN THE HEART) PDHP is inactivated by \_\_\_\_\_\_\_
PDHP is inactivated by _High NADH/NAD+_ PDHP - pyruvate dehydrogenase phosphatase - activates PDH by dephosphorization to make acetyl coA from pyruvate High NADH/NAD+ provide neg feedback
58
(REGULATION OF GLUCOSE OXIDATION IN THE HEART) PDHK is activated by __________ and \_\_\_\_\_\_\_\_\_\_\_
PDHK is activated by _high acetyl CoA/CoA_ and _High NADH/NAD+_ To decrease conversion of pyruvate to acetyl CoA
59
What are the four components of Fatty Acid Metabolism?
1. Cellular uptake and activation 2. Triacylglycerol (TAG) synthesis/mobilization 3. Mitochondrial uptake 4. Mitochondrial beta-oxidation
60
What are the four components of Glucose Metabolism?
1. Glucose Uptake 2. Glycogen synthesis/mobilization 3. Glycolysis 4. Glucose oxidation
61
How are fatty acids delivered to the cell?
Either bound to serum albumin or as triacylglycerol bound to lipoproteins or chylomicrons
62
\_\_\_\_\_\_\_ is the primary acid transporter that mediates cellular fatty acid uptake (~50%)
_CD36_ is the primary acid transporter that mediates cellular fatty acid uptake (~50%) CD36 = cluster of differentiation 36
63
What is CD36?
_CD36_ is the primary acid transporter that mediates cellular fatty acid uptake (~50%) cluster of differentiation 36
64
Fatty acids must first be activated via _____________ prior to any type of metabolism
Fatty acids must first be activated via _esterification to CoA (via FACS)_ prior to any type of metabolism * FACS - fatty acyl CoA synthetase
65
3 metabolic fates of fatty acids after esterification via FACS to Fatty acyl CoA?
* Storage as TAG * Membrane synthesis * beta-oxidation TAG = triacylglycerol
66
What is the composition of Triacylglycerol (TAG)?
TAG is composed of a glycerol-3-phosphate backbone attached to 3 activated fatty acids
67
\*\*\*IMAGE FROM SLIDE 32\*\*\* How is Triglyceride/triacylglycerol (TAG) synthesized?
3 different acyltransferases each add one fatty acid to the glycerol-3-phosphate backbone GPAT is the rate-limiting enzyme for TAG synthesis
68
\_\_\_\_\_\_is the rate-limiting enzyme for TAG synthesis
_GPAT_ is the rate-limiting enzyme for TAG synthesis GPAT = glycerol-3-phosphate acyltransferase Catalyzes conversion of Acyl Coa to LPA (lysophosphatidate)
69
What is involved in TAG mobilization?
TAG mobilization involves the release of the 3 fatty acids attached to the glycerol-3-phosphate * 3 different lipase enzymes are involved in releasing 1 free fatty acid at a time * the released free fatty acids need to be activated before they can be metabolized
70
The heart stores more fat as _______ before it's converted in the mitochondria
The heart stores more fat as _TAG_ before it's converted in the mitochondria
71
Long chain fatty acids require a ________ to enter the mitochondria
Long chain fatty acids require a _carnitine shuttle_ to enter the mitochondria * (because Long-chain CoA is impermeable to membranes
72
\_\_\_\_\_\_\_ is the rate limiting enzyme for fatty acid **oxidation**
_CPT-1_ is the rate limiting enzyme for fatty acid **oxidation** * converts a CoA ester into **acylcarnitine** * **CPT =** Carnitine palmitoyltransferase
73
Once acylcarnitine has entered the mitochondria ________ reconverts it back into a CoA ester for subsequent \_\_\_\_\_\_\_\_\_\_
Once acylcarnitine has entered the mitochondria _CPT-2_ reconverts it back into a CoA ester for subsequent _beta-oxidation_ * reverses action of CPT-1 * CPT = carnitine palmitoyltransferase
74
Function of CPT-1
CPT-1 (carnitine palmitoyltransferase) convert CoA ester into acylcarnitine so that it can enter the mitochondria
75
Function of CPT-2?
CPT-2 (carnitine palmitoyltransferase 2) converts acylcarnitine back into CoA ester (long-chain CoA) - essentially reversing the action of CPT-1
76
\_\_\_\_\_\_\_\_ inhibits CPT-1
_Malonyl CoA_ inhibits CPT-1 (recall: CPT-1 converts CoA Ester into acylcarnitine so that it can be transported across the mitochondrial membrane)
77
Malonyl CoA is synthesized by _____ and degraded by \_\_\_\_\_
Malonyl CoA is synthesized by _ACC_ and degraded by _MCD_ * ACC - acetyl CoA carboxylase * MCD - malonyl CoA decarboxylase
78
Relevance of Malonyl CoA during feeding and starvation: Insulin activates \_\_\_\_\_\_\_ Glucagon activates \_\_\_\_\_\_\_
Insulin activates _ACC_ * ACC synthesizes Malonyl CoA which inhibits CPT-1 to prevent transport of Fatty Acyl CoA into mitochondria Glucagon activates _AMPK_ * AMP activated protein kinase = inhibits ACC during ischemia (fat is less oxygen efficient than carbs) * AMPK -| ACC → Malonyl CoA -| CPT-1 → transport of Fatty acyl CoA into mito * (increase transport of Fatty Acyl CoA)
79
Activation of AMPK during ischemia causes:
Activation of AMPK during ischemia inhibits ACC * allows fatty acid oxidation to remain the main fuel for residual O2 consumption
80
(MITOCHONDRIAL FATTY ACID OXIDATION) beta-oxidation progressively cleaves _______ from \_\_\_\_\_\_
(MITOCHONDRIAL FATTY ACID OXIDATION) beta-oxidation progressively cleaves _off 2-carbon acetyl CoA units_ from a _fatty acyl CoA_
81
* (MITOCHONDRIAL FATTY ACID OXIDATION)* * beta-oxidation progressively cleaves _off 2-carbon acetyl CoA units_ from a _fatty acyl CoA_* * What happens to the generated acetyl CoA?
The generated acetyl coa enters the Krebs Cycle to produce **reducing equivalents** (FADH2/NADH)
82
The __________ enzymes of beta-oxidation produce NADH and FADH2 which donate their electrons directly to the e- transport chain
The _dehydrogenase_ enzymes of beta-oxidation produce NADH and FADH2 which donate their electrons directly to the e- transport chain * these enzymes are inhibited in high energy states (eg high NADH)
83
Which enzymes of the beta-oxidation spiral are inhibited in high energy states?
The dehydrogenase enzymes of beta-oxidation are inhibited when energy is high (no need to produce more NADH/FADH2)
84
\*\*\*\*\*SLIDE 37 IMAGE\*\*\*\*\*\* How does the image provide evidence of the randal cycle?
As you increase the [fatty acids] delivered to the heart, a corresponding increase in fatty acid oxidation is observed which is associated with a corresponding reduction in glucose oxidation
85
What are the three components of Myocardial Ketone body metabolism?
1. Ketogenesis (doesn't occur in the heart) 2. Ketone body uptake 3. Ketone body beta-oxidation
86
Ketone bodies are generated in the _______ during periods of \_\_\_\_\_- to provide fuel for the brain (brain cannot oxidize fatty acids)
Ketone bodies are generated in the _liver_ during periods of _starvation_ (low carb)- to provide fuel for the brain (brain cannot oxidize fatty acids)
87
What are the 2 primary ketone bodies in the circulation?
1. Acetoacetate (AcAc) 2. beta-hydroxybutyrate (betaOHB)
88
AcAc and *beta*OHB (the primary ketone bodies in the circulation) are transported out and into cells via \_\_\_\_\_\_\_\_\_\_
AcAc and betaOHB (the primary ketone bodies in the circulation) are transported out and into cells via monocarboxylic transporters (MCTs) * may also be transported via diffusion
89
\_\_\_\_\_\_\_ is the rate-limiting enzyme of ketone body oxidation
_SCOT_ is the rate-limiting enzyme of ketone body oxidation SCOT = succinyl CoA:3-ketoacid CoA transferase
90
Function of Succinyl CoA?
Succinyl CoA provides CoA to AcAc to activate it for oxidation as AcAc-CoA (AcAc = Acetoacetate)
91
Which enzyme hydrolyzes AcAc-CoA into 2 molecules of acetyl CoA?
mitochondrial (m) thiolase - hydrolyzes AcAc-CoA into 2 molecules of acetyl CoA (that can enter the krebs cycle for subsequent generation of ATP)
92
Why is there no SCOT enzyme in the liver?
SCOT oxidizes ketone bodies - wouldn't want SCOT present because it would oxidize the ketone bodies produced by the liver before they could be delivered to other tissues
93
Why does *beta*OHB produce more energy/ATP than AcAc?
Because *beta*OHB generates an NADH at the *beta*OHB dehydrogenase (BDH1) step (conversion of betaOHB to AcAc by BDH1) in extrahepatic mito
94
What are two enzymes specific to the ketone pathway?
HMGCS2 SCOT
95
Oxidative metabolism of all substrates results in the production of \_\_\_\_\_\_\_\_
Oxidative metabolism of all substrates results in the production of _acetyl CoA_ important because Aceyl CoA is a critical intermediate for the Krebs cycle
96
Krebs cycle results in the production of \_\_\_\_\_\_\_\_\_
Krebs cycle results in the production of _reducing equivalents (NADH and FADH2)_
97
Majority of energy harvested from oxidation of any nutrient occurs where?
Krebs cycle
98
What are the four dehydrogenase enzymes that generate reducing equivalents
1. Isocitrate dehydrogenase 2. alpha-ketoglutarate dehydrogenase 3. Succinate dehydrogenase 4. Malate dehydrogenase
99
Function of Isocitrate dehydrogenase in the krebs cycle
Isocitrate dehydrogenase catalyzes the **oxidative decarboxylation** of Isocitrate into alpha-ketoglutarate and in the process makes NADH + H+ + CO2
100
Function of alpha-ketoglutarate dehydrogenase
Catalyzes conversion of alpha-ketoglutarate into Succinyl CoA * produces NADH, H+ and CO2
101
Function of Succinate Dehydrogenase?
Catalyzes the oxidation of succinate into Fumarate FADH is reduced to FADH2
102
Function of Malate Dehydrogenase
Malate dehydrogenase catalyzes the conversion of Malate to oxaloacetate (via oxidation of the hydroxyl group on Malate) NAD is reduced to NADH and a proton H+ is produced

PHYSL 404 - Cardiovascular Physiology (17 decks)

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