Chapter 27 - Fatty Acid Degradation

How are fatty acids stored?

As triacylglycerols

• Connected to glycerol

• Triacylglycerols are stored in lipid droplets in adipose tissue

What are the 3 stages of processing FA in triacylglycerols?

1. Triacylglycerol gets degraded to release FA and glycerol into blood

2. FA are activated then transported into mitochondria for oxidation

3. FA are degregraded into acetyl CoA for use in TCA

How are the triacylglycerols stored in adipose tissue?

In adipocytes

• collected in a lipid droplet

What triggers the breakdown of triacylglycerol?

Lipolysis

• Epinephrine and glucagon trigger it

• E is released during stress/exercise and glucagon when blood sugar is low, triacylglycerol is long term energy storage

• both hormones make sense for the degradation

What is the process of triacylglycerol degradation?

1. Protein kinase A phosphorylates perilipin

   • this restructures the lipid droplet and activates ATGL

2. Activation of ATGL cleaves TAG, into DAG

3. Hormone-sensitive (HS) lipase cleaves the DAG into MAG

4. MAG lipase cleaves MAG

   • Producing:

     • 1 glycerol

     • 1 FAT

What happens after triacylglycerol breakdown?

• FA released from TAGs are released into blood, binding to albumin

• Glycerol gets absorbed by liver and is used in glycolysis and gluconeogenesis

What happens in preparation of degradation?

They must be activated by linking to Coenzyme A (CoA)

• intermediate acyl-adenylate is formed during activation

• process is driven forward by pyrophosphatase

How are FA importanted into the mitochondria?

After FA are activated, they are transferred to carnitine

• catalyzed by carnitine acyltransferase I

What are the four repeated steps of Fatty acid degradation?

OHOT

• Oxidation

• Hydration

• Oxidation

• Thiolysis

What happens during the first oxidation OHOT?

A doubled is created between C-2 and C-3

• product: trans-Δ2-Enoyl CoA

• Electrons get taken up by FAD generating FADH2

  • rxn is catalyzed by acyl CoA dehydrogenase

What happens during hydration OHOT?

Hydration of the enoyl CoA double bond generates a hydroxyl group on the β carbon

• product: L-3-hydroxyacyl CoA

• rxn is catalyzed by enoyl CoA hydratase

What happens during the second oxidation OHOT?

Second oxidation converts β carbon, (C-3) into a keto group

• product: 3-ketoacyl CoA

• Electrons get taken up by NAD+, generating NADH

• rxn is catalyzed by L-3-hydroxyacyl CoA dehydrogenase

What happens during Thiolysis OHOT?

The keto group, ketoacyl CoA gets cleaved generating an acetyl CoA

• product: an acyl CoA two carbons shorter than the beginning of the cycle

• rxn catalyzed by thiolase

Why does β-oxidation occur in the mitochondria?

The products get used immediately in the TCA and the ETC

What is the net reaction for one round of β-oxidation?

Cn-acyl CoA + FAD + NAD+ + H2O + CoA → Cn-1 acyl CoA + FADH2 + NADH + acetyl CoA + H+

What is the need reaction for complete β-oxidation of (C-16) palmitoyl CoA?

Palmitoyl CoA + 7 FAD + 7 NAD+ + 7 CoA + 7 H2O → 8 acetyl CoA + 7 FADH2 + 7 NADH + 7 H+

• generates 106 molecules of ATP

Why is the standard OHOT not sufficient for degrading unsaturated FAs?

The first three steps proceed normally..

• but C3-C4 double bond is not the normal substrate for acyl CoA dehydrogenase

• instead an isomerase is to move the double bond and a reductase

  • results in trans double bond at C2-C3

  • produce is normal substrate for hydratase, (H in OHOT)

  • step is required for all double bonds at C3

What happens if the double bond in an unsat. FA is at an odd numbered position?

Only the isomerase is required to return to OHOT

What does odd numbered carbon mean?

You only need the isomerase

What does even numbered carbon mean?

You need both the isomerase and reductase

What happens with FA with odd numbers of total carbons?

They must also be processed

• small fraction of total FA population, small amounts in vegetables

• degradation leaves a three carbon propionyl CoA after last cleavage

• Three carbon residue is processed into succinyl CoA (four carbons)

What happens to most acetyl CoA created via degradation?

It is used in TCA

What happens to the rest of the acetyl CoA created during degradation?

It can be used to generate ketone bodies, alt fuel source in absence of glucose

• soluble

Where is the major site of ketone body production?

Ketogenesis

• In liver mitochondria

  • get secreted into blood for use of fuel

Why do liver cells lack CoA transferase?

So the liver does not use up the ketone bodies it creates

• instead sends them to other tissues that need energy

What are the limitations in fatty acid metabolism?

FA cannot be converted into glucose

• creates a metabolic challenge when glycogen stores are depleted

Why are ketone bodies important?

Very important when glucose stores are depleted

• brain will switch to use ketone bodies are an important fuel source

• In the liver, production is increased as entry into TCA declines