25 - Fat Catabolism

Question 1

What do adipocytes do when the body needs energy?

Answer 1

Hydrolyzes triacylglycerols (lipolysis) and releases the resulting fatty acids and glycerol

Question 2

What two lipases are involved in lipolysis?

Answer 2

adipose triglyceride lipase (ATGL)

Hormone sensitive lipase (HSL)

Question 3

What activates ATGL (adipose triglyceride lipase)?

Answer 3

Glucagon
Epinephrine

Glucagon promotes energy mobilization

Question 4

What inactivates HSL (Hormone sensitive lipase)?

Answer 4

Insulin inactivates it

Insulin promotes energy storage

Question 5

Fatty acids are almost never found free in circulation, what protein do they bind to after hydrolysis of TG?

Answer 5

Albumin

Question 6

After hydrolysis of TG in adipocytes by lipases, where do the 3 fatty acids go and where does the glycerol go?

Answer 6

3 fatty acids: muscle and liver

Glycerol: liver

Question 7

TG is at its barest, what two ingredients?

Answer 7

3 fatty acids

1 glycerol-3-phosphate

Question 8

Describe the breakdown of triacylglycerol in terms of intermediates and by products

Answer 8

Triacylglycerol - diacylglycerol (releases a fatty acid)

Diacylglycerol to monoacylglycerol (releases fatty acid)

monoacylglycerol to glycerol (releases fatty acid)

Question 9

How does glucagon and epinephrine stimulate triacylglycerol hydrolysis?

Answer 9

1. They bind to a hormon-receptor on an adipocyte, causing a conformational change that activates adenylate cyclase
2. Adenylate cyclase produces cAMP from ATP
3. cAMP activates protein kinase
4. Protein kinase uses ATP to phosphorylate triacylglycerol lipase (activating it)

Question 10

What deactivates triacylglycerol lipase?

Answer 10

A phosphatase with a Mg ion

Question 11

What happens to glycerol in the liver?

Answer 11

The liver uses glycerol in glycolysis or gluconeogenesis, depending on its need

The liver breaks it down into L-glycerol. Then into L-glycerol-3-phosphate with glycerol kinase. Then into dihydroxy-acetone phosphate with glycerol-3-phosphate dehydrogenase

Dihydroxy-acetone phosphate is the form of glycerol that can undergo glycolysis or gluconeogenesis

Question 12

What happens to fatty acids once they are in blood circulation (after being released form adipocytes)?

Answer 12

Fatty acids can be broken down by nearly any tissue (except brain and red blood cells)

Question 13

How are fatty acids converte to acetyl-CoA, producing NADH and FADH2 on the side?

Answer 13

1. Fatty acids are joined to a CoA with the hydrolysis of an ATP to AMP + PPi (in the cytosol)
2. Fatty acyl-CoA is then transported into the mitochondrial matrix where it is oxidized to acetyl-CoA, one NAD+ and one FAD are reduced in the process to NADH and FADH2

Question 14

Where are fatty acids oxidized?

Answer 14

In the mitochondria

Question 15

Which carbons are removed with each cycle of fatty acid oxidation?

Answer 15

Each reaction cycle removes 2 carbon atoms from beginning of the chain with the carboxy group

Question 16

How is fatty acid oxidation regulated?

Answer 16

Through transport of fatty acids into mitochondria

Question 17

Energy production from fatty acids requires what element?

Answer 17

oxygen

Question 18

What is step 1 of fatty acid oxidation? (β-oxidation)? Where do the products end up? (begins in cytosol)

Answer 18

Activation

Fatty acids are activated in the cytosol by the conjugation to coenzyme A (CoA)

This step costs 1 ATP and Acyl-CoA synthetase is the enzyme used (embedded into outer membrane of mitochondria). Acyl-CoA is in intermembrane space of mitochondria at this point.

Question 19

What is step 2 of fatty acid oxidation? (begins in cytosol/intermembrane space of mitochondria)

Answer 19

Transport into the mitochondrial matrix

Carnitine acyltransferase converts a carnitine into acylcarnitine, releasing CoA as CoASH into the intermembrane space.

Acylcarnitine (fatty acid + carnitine) is then carried by a protein into the mitochondrial matrix.

In the mitochondrial matrix acyl-carnitine is broken down into carnitine and acyl-CoA (with the addition of CoASH). Acyl-CoA is then in the mitochondrial matrix and ready for breakdown.

Question 20

What is step 3 of fatty acid oxidation? (begins in mitochondrial matrix)

Answer 20

1. In the mitochondrial matrix acyl-CoA is broken down by acyl-CoA dehydrogenase to form trans-α, β-enoyl-CoA, reducing an FAD to a FADH2 in the process.
2. Trans-α, β-enoyl-CoA is then converted by anoyl-CoA hydrolase to form L-β-hydroxyacyl-CoA, using an H2O
3. See summary below…

In other terms,

1. There is formation of double bond between alpha and beta carbon of the fatty acid chain by acyl-CoA dehydrogenase. Formation of FADH2
2. Hydration of the double bond, forming a hydroxyl group on the beta carbon.
3. Dehydrogenation by 3-L-hydroxyacyl-CoA dehydrogenase forming a ketogroup at the beta carbon and NADH
4. Carbon-carbon cleavage between the α and β-carbon by β-keoacyl-CoA thiolase, shortening the chain by 2 carbons and forming acetyl CoA. Fatty acid chain is degraded from carboxy side, nor from the end.

Question 21

What is the total amount of ATP made from the full oxidation of palmitate? (C16:0)

Answer 21

106 ATP

6.6 ATP per carbon

Question 22

How many rounds of oxidation can a 16 carbon fatty acid with no double bonds (palmitate) undergo? How much NAD+, FAD, CoASH and H2O is needed?

Answer 22

7 rounds of β-oxidation.

7 FAD
7 NAD+
7 CoASH
7 H20

Produces:
7 NADH
7 FADH
8 Acetyl-CoA

2 ATP is needed for activation with CoA

Question 23

Without the presence of oxygen, what provides greater energy yields, oxidation of fatty acids or oxidation of glucose? With oxygen? Why?

Answer 23

Oxidation of fatty acids, because fatty acids are more reduced.

However, glucose can make some ATP without oxygen in the cytosol, where fatty acids cannot generate any ATP without oxygen. Therefore, per oxygen more ATP is made form glucose.

Question 24

Describe the oxidation of very long chain fatty acids

Answer 24

Oxidation in peroxisomes to medium-chain fatty acids, which are then oxidized in the mitochondria. Peroxisomal fatty acid oxidation does not yield ATP.

Question 25

Describe oxidation of unsaturated fatty acids

Answer 25

Additional enzymes are required to degrade the carbon around double bonds. Odd-numbered double bonds requires an isomerase, even-numbered bonds require a dehydrogenase. Energy yield is lower than from saturated fatty acids.

Question 26

Describe the oxidation of odd chain fatty acids

Answer 26

Oxidation yields propionic acid, which is converted to succinyl CoA. This is the only way that part of a fatty acid can be glucogenic (intermediate in TCA cycle)

Question 27

Describe the oxidation of branched chain fatty acids

Answer 27

Occur in dairy products and products derived from herbivores. Branch points in the carbon chain prevents β-oxidation. Branched chain fatty acids are broken down by α-oxidation

Question 28

How does vitamin B12 deficiency cause neurological damage?

Answer 28

Because of the accumulation of odd-chain fatty acids in the neuronal membranes.

Vitamin B12 plays a part in odd-chain fatty acid oxidation to make succinyl-CoA

Question 29

Describe the steps in the αoxidation of phytanic acid (a branched chain fatty acid) to pristanic acid. What happens to this pristanic acid?

Answer 29

1. Phytanic acid is converted to phytanoyl-CoA
2. Oxidation by hydroxylase using oxygen
3. Decarboxylation requires TPP cofactor, pristanic acid is made

Pristanic acid is then added to CoA with acyl-CoA synthetase, which goes through 6 cycles of β-oxidation.

What results is:
acetyl-CoA
Propionyl-CoA
isobutyl-CoA

Question 30

What three products come out of the α-oxidation of phytanic acid (branched chain amino acid) to pristanic acid. And then 6 cycles of β-oxidation of pristanic acid?

Answer 30

Acetyl-CoA
Propionyl-CoA
Isobutyl-CoA

Question 31

What are ketone bodies and why are they made?

Answer 31

Ketone bodies are fatty acid-derived energy that can be used by the brain.

They are made because fatty acids cannot be converted into glucose and the brain cannot use fatty acids as fuel

Question 32

Can fatty acids be converted into glucose?

Answer 32

No

Question 33

When does ketogenesis occur? What is it?

Answer 33

Occurs:

1. When there is limited glucose supply (sever days of fasting, no more liver glycogen, gluconeogenic substrates getting used up).
2. Excess fatty acids
3. Untreated diabetes

Basically it occurs when there is limited glucose and gluconeogenic substrates. It occurs in the liver and results in the formation of ketone bodies.

Question 34

When is acetyl CoA converted to ketone bodies?

Answer 34

When there is a depletion of TCA cycle intermediates resulting in acetyl CoA buildup (because fatty acid breakdown cannot be fully oxidized in TCA cycle).

Question 35

What are the three endogenous ketone bodies?

Answer 35

The three endogenous ketone bodies are acetone, acetoacetic acid, and beta-hydroxybutyric acid (D-β-Hydroxybutyrate)

D-β-Hydroxybutyrate and acetoacetate are used by the heart and brain as energy, but acetone is a waste product that is excreted

Acetone is produced by spontaneous decarboxylation of acetoacetate, meaning this ketone body will break down in five hours if it is not needed for energy and be removed as waste. This “use it or lose it” factor contributes to much of the weight loss found in ketogenic diets. Acetone cannot be converted back to acetyl-CoA, so it is excreted in the urine, or (as a consequence of its high vapor pressure) exhaled. Acetone is responsible for the characteristic “Sweet & fruity” odor of the breath of persons in ketoacidosis.[7]

Question 36

How are ketone bodies made?

Answer 36

Ketone bodies are produced from acetyl-CoA (see ketogenesis) mainly in the mitochondrial matrix of hepatocytes when carbohydrates are so scarce that energy must be obtained from breaking down fatty acids. Because of the high level of acetyl CoA present in the cell, the pyruvate dehydrogenase complex is inhibited, whereas pyruvate carboxylase becomes activated. High levels of ATP and NADH inhibit the enzyme isocitrate dehydrogenase in the TCA cycle and as a result cause an increase in the concentration of malate (due to the equilibrium between itself and oxaloacetate). The malate then leaves the mitochondrion and undergoes gluconeogenesis. The elevated level of NADH and ATP result from β-oxidation of fatty acids.[6] Unable to be used in the citric acid cycle, the excess acetyl-CoA is therefore rerouted to ketogenesis. Such a state in humans is referred to as the fasted state.

Question 37

What happens to acetoacetate once it is made in the liver?

Answer 37

There are no CoA transferases in the liver, so it is transported out to tissues that need energy from this ketone body

Question 38

What does D-3-Hydroxybutyrate dehydrogenase due?

Answer 38

Converts β-hydroxybutyrate to acetoacetate by reducing a NAD to NADH, which can be transported out of the liver to have an CoA added with CoA transferase and succinyl CoA, forming acetoacetyl CoA.

Acetoacetyl CoA is catalyzed by thiolase into acetyl CoA, which can be fed into the TCA cycle to provide energy for the cell

Question 39

How are ketone bodies used as fuel?

Answer 39

1. COnverted by D-3-Hydroxybutyrate dehydrogenase into acetoacetate in the liver. NAD+ is reduced to NADH
2. Acetoacetate is transported to tissue outside liver (eg. brain, heart)
3. CoA transferase uses a succinyl CoA to convert acetoacetate into acetoacetyl CoA
4. Thiolase uses CoA and converts acetoacetyl CoA into 2 Acetyl CoA ‘s
5. These two acetyl CoA can be put into TCA cycle

Question 40

Why is it better to consume odd-numbered fatty acids than even number, when fasting carbohydrates?

Answer 40

When fasting carbohydrates, glycolysis slows and less pyruvate is made. This means that pyruvate cannot regenerate oxaloacetate and keep TCA cycle going. Consequence is increased rate of beta oxidation of fatty acids and leading to ketosis.

Beta oxidation produces two acetyl CoA molecuels from even numbered fatty acids, or propionyl-CoA and acetyl-CoA from odd numbered fatty acids.

Propionyl-CoA can be converted to succinyl-CoA, which when converted to oxaloacetate will stimulate the citric acid cycle again.

There is an accumulation of acetyl-CoA, so eating even numbered fatty acids would only bring the cell closer to ketosis.

Question 41

Adipocytes do not take up glycerol. They use it to store TG though. Where do they get their glycerol for storing fatty acids as TG if they can’t take it up?

Answer 41

Glucose from the diet. Dietary glucose is broken down by glycolysis in adipocytes and the resulting 3-phosphoglycerol is used for TG synthesis.