Biochem Lecture 21 Fatty Acid Metabolism

We discussed in detail how to use beta-oxidation to break down palmitate 16C FAs, but what about Long Chain 20-22C FAs?

Long chain FAs about 20-22Carbons will need to undergo beta-oxidation first in peroxisomes, then within the mitochondria.

Describe Acetyl CoA Synthase and how biotin and ATP are involved.

Acetyl CoA Synthase is the rate limiting step enzyme that basically produces every Malonyl CoA that will be added onto the FA chain. -Acetyl CoA Synthase will take Acetyl CoA and convert it into Malonyl CoA by using CO2, Biotin, and ATP.

What are the two reasons we need a translocase for Fatty Acid-Carnitine within the inner membrane?

1) Carnitine is polar so we need a translocase to help push the polar molecule through 2) Translocase prevents the Fatty-Acid Carnitine complex from getting stuck within the membrane.

What is CD43 and what does it do?

CD43 is a Fatty Acid translocase and it will work with Fatty Acid Binding Protein to transport circulatory FAs into the cell through the plasma membrane.

What is the reason that Fatty Acyl-CoA has its CoA group swapped out for Carnitine by the outermembrane enzyme Carnitine Palmitoyl-Transferase I?

Carnitine-Palmitoyl Transferase I exchanges Fatty Acyl-CoA for Fatty Acyl-Carnitine because they is no inner membrane Translocase for CoA but there is one for Carnitine. -This is the only way that the Fatty Acid can make its way into the mitochondrial matrix by passing the inner membrane.

What is the difference between Chylomicron TAGs and VLDL TAGs since they are both lipoprotein particles?

Chylomicron TAGs are derived from the GI tract and are dietary TAGs VLDL carry endogenously synthesized TAGs from the liver.

True or false: the FAs freed from HSL in adipose tissue with travel in circulation via Chylomicrons as well.

FALSE!!!! FAs freed by HSL in adipose tissue travel through circulation by lipid carrier albumin.

In cases where we digest microbes that give us odd chained Fatty Acids, what would occur and what is the significance of Propionyl CoA and Succinyl CoA?

If we digest odd chained FAs, after the last alpha-beta carbon cleavage of the FA chain, we will end up with Propionyl CoA, a three Carbon molecule. -Propionyl CoA will then interact with Biotin and Vitamin B12 CoEnzyme to create Succinyl CoA, and Succinyl CoA will then be able to feed into the TCA cycle and push metabolism towards Gluconeogenesis -however, note that this push towards Gluconeogenesis is not really strong enough to get that pathway started.

How is Ketoacidosis caused and why are Type I diabetics more susceptible to it?

Ketoacidosis is caused when you have a large concentration of ketone bodies within circulation which causes a drop in blood pH which isn't harmful if you are well-hydrated because then you can just filter the ketones through your kidneys. However, TypeI Diabetics have issues with hydration and therefore are more vulnerable to ketoacidosis.

Why are Ketone bodies made?

Ketone Bodies are produced because HSL releases twice as much FAs as we actually need everytime it is signaled to cleave FAs. Therefore, the excess FAs in circulation will reach the Liver where Ketone Body synthesis takes place.

True or false: If you have unsaturated FAs undergoing Beta-Oxidation, you would have less ATP yield from that FA as compared to saturated FA.

TRUE!! -This is because if the double bond already exists, then we don't need FAD+ to oxidize and steal electrons to create double bonds between the alpha and beta carbons if it is already there. -this may seem convenient, however, note that the FADH2 is no longer created if this is the case. Therefore less FADH2 would be used to generate ATP in the ETC. -the ATP yield decrease is not too significant though

True or false: Glucagon and epinephrine will act as inhibitory hormones to Acetyl-CoA Carboxylase to prevent Fatty Acid/palmitate synthesis.

TRUE.

True or false: HMG CoA Synthase is a Liver Mitochondrial ONLY enzyme which is the rate limiting enzyme in ketone body production.

TRUE.

True or false: Ketone Bodies are only made in the Liver.

TRUE.

True or false: Fatty acid metabolism is mainly active in the Fasting state.

TRUE. FA metabolism is mainly active in the fasting state because we are taking energy from storage. Otherwise, if we just ate, we would be feeding the TCA cycle with glucose to acetyl CoA, not FAs to acetyl CoA

True or false: Everytime you synthesize FAs, you make 16:0 Palmitate.

TRUE. The only way to elongate or desaturate the FA is use: -microsomal elongase system to elongate the FA -Fatty Acyl CoA Desaturase to desaturate the FA.

What is the rate limiting step in fatty acid oxidation?

The Hormone Sensitive Lipase is the rate limiting step in beta oxidation of fatty acids.

How is Ketone Body futile cycle prevented? How is Thiophorase involved?

The Liver produced Ketone Bodies for energy digestion mainly by the brain, and the Liver is capable of preventing a futile cycle where the Liver will just consume the ketone body immediately The Liver prevents Ketone Body futile cycles because it LACKS the enzyme Thiophorase which actually digests the Ketone Bodies for energy.

What is another role of VLDL besides carrying endogenously synthesized TAGs from the liver?

VLDL may also carry TAGs that were made from FFAs if we are switching from fasting to FED state because then we no longer need FAs to be broken down for energy because we are entering the glycolytic pathway.

What enzyme is the Rate Limiting step in Ketone Body synthesis catalyzed by?

The rate limiting step in ketone body synthesis is catalyzed by HMG CoA Synthase where we turn AcetoAcetyl-CoA (2 Acetyl CoAs) into 3-Hydroxy-3-MethylGlutaryl CoA (HMG CoA).

True or false: Once FAs reach the cytosol of the target cell, Fatty Acyl-CoA Synthase will add a CoA group onto the FA so that it can be recognized by the Carnitine Shuttle Transferases.

True!! Additionally, remember that Fatty Acyl CoA Synthase requires 2 ATP to add on a CoA group to FA.

True or false: Carnitine Palmitoyl Transferase I carnitine shuttle prevents the futile cycle by placing the carnitine onto the Fatty Acid.

True.

True or false: Epinephrine will activate HSL to begin freeing FAs.

True.

True or false: The only two sources of free fatty acids for FA metabolism will come from either HSL FAs from adipose tissue or LPL FAs from circulating Chylomicrons.

True.

True or false: The process of adding an Acyl-CoA group onto FAs by FA-Acyl-CoA synthase, costs 2 ATP.

True.

True or false: You need beta-oxidation to have ketone body synthesis because it will produce enough Acetyl-CoA KB synthesis in the first place.

True.

True or false: every FA that we synthesize is made using Acetyl CoA, and therefore we only synthesize even numbered chain FAs.

True.

True or false: You need beta-oxidation to allow ketone body synthesis to function properly.

True. -otherwise how would you produce acetyl CoA from FFAs in circulation to feed into ketone body metabolism

Describe why Ketone Bodies are important to manufacture in fasting states.

When we fast, we begin to run low on blood glucose concentrations, meaning that we need another form of energy to be able to pass the blood-brain barrier and feed the brain's energy needs. Therefore, we use the excess circulating concentration of FAs created by HSL release from Adipose tissue, and we utilize our liver to perform beta oxidation which will break down those FAs into Acetyl CoAs. Those excess Acetyl CoAs will then be converted to Ketone bodies which can act as a BLOOD-GLUCOSE SUBSTITUTE for the brain to use energy.