Flashcards in 25 - Fat Catabolism Deck (41):
What do adipocytes do when the body needs energy?
Hydrolyzes triacylglycerols (lipolysis) and releases the resulting fatty acids and glycerol
What two lipases are involved in lipolysis?
adipose triglyceride lipase (ATGL)
Hormone sensitive lipase (HSL)
What activates ATGL (adipose triglyceride lipase)?
Glucagon promotes energy mobilization
What inactivates HSL (Hormone sensitive lipase)?
Insulin inactivates it
Insulin promotes energy storage
Fatty acids are almost never found free in circulation, what protein do they bind to after hydrolysis of TG?
After hydrolysis of TG in adipocytes by lipases, where do the 3 fatty acids go and where does the glycerol go?
3 fatty acids: muscle and liver
TG is at its barest, what two ingredients?
3 fatty acids
Describe the breakdown of triacylglycerol in terms of intermediates and by products
Triacylglycerol - diacylglycerol (releases a fatty acid)
Diacylglycerol to monoacylglycerol (releases fatty acid)
monoacylglycerol to glycerol (releases fatty acid)
How does glucagon and epinephrine stimulate triacylglycerol hydrolysis?
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)
What deactivates triacylglycerol lipase?
A phosphatase with a Mg ion
What happens to glycerol in the liver?
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
What happens to fatty acids once they are in blood circulation (after being released form adipocytes)?
Fatty acids can be broken down by nearly any tissue (except brain and red blood cells)
How are fatty acids converte to acetyl-CoA, producing NADH and FADH2 on the side?
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
Where are fatty acids oxidized?
In the mitochondria
Which carbons are removed with each cycle of fatty acid oxidation?
Each reaction cycle removes 2 carbon atoms from beginning of the chain with the carboxy group
How is fatty acid oxidation regulated?
Through transport of fatty acids into mitochondria
Energy production from fatty acids requires what element?
What is step 1 of fatty acid oxidation? (β-oxidation)? Where do the products end up? (begins in cytosol)
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.
What is step 2 of fatty acid oxidation? (begins in cytosol/intermembrane space of mitochondria)
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.
What is step 3 of fatty acid oxidation? (begins in mitochondrial matrix)
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.
What is the total amount of ATP made from the full oxidation of palmitate? (C16:0)
6.6 ATP per carbon
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?
7 rounds of β-oxidation.
2 ATP is needed for activation with CoA
Without the presence of oxygen, what provides greater energy yields, oxidation of fatty acids or oxidation of glucose? With oxygen? Why?
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.
Describe the oxidation of very long chain fatty acids
Oxidation in peroxisomes to medium-chain fatty acids, which are then oxidized in the mitochondria. Peroxisomal fatty acid oxidation does not yield ATP.
Describe oxidation of unsaturated fatty acids
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.
Describe the oxidation of odd chain fatty acids
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)
Describe the oxidation of branched chain fatty acids
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
How does vitamin B12 deficiency cause neurological damage?
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
Describe the steps in the αoxidation of phytanic acid (a branched chain fatty acid) to pristanic acid. What happens to this pristanic acid?
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:
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?
What are ketone bodies and why are they made?
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
Can fatty acids be converted into glucose?
When does ketogenesis occur? What is it?
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.
When is acetyl CoA converted to ketone bodies?
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).
What are the three endogenous ketone bodies?
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.
How are ketone bodies made?
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. 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.
What happens to acetoacetate once it is made in the liver?
There are no CoA transferases in the liver, so it is transported out to tissues that need energy from this ketone body
What does D-3-Hydroxybutyrate dehydrogenase due?
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
How are ketone bodies used as fuel?
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
Why is it better to consume odd-numbered fatty acids than even number, when fasting carbohydrates?
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.