Fatty Acid Catabolism

Fatty Acid Catabolism

Stages in Catabolism of Fatty Acids

1. Release of Fatty Acids from TAG (Triacylglycerols)

   • Endogenous TAG stores in adipocytes are broken down by lipases (ATGL, HSL, MGL), releasing fatty acids into the bloodstream.
   • TAG carried in lipoproteins are broken down by extracellular lipase (LPL) in capillaries to release fatty acids. (covered in lecture 14)
   • $TAG \rightarrow FA$

2. Uptake of Fatty Acids

   • Fatty acid transporters move fatty acids across the plasma membrane into cells.
   • Key transporters:
     • FAT/CD36: Found in adipose tissue, heart, and skeletal muscle; translocates from intracellular vesicles to the plasma membrane.
     • FATP1-6: Widespread; associated with fatty acyl-CoA synthetase.
     • FABPpm: Widespread; recruits FA to the plasma membrane.

3. Transport into Mitochondria: Conversion to Acyl-CoA

   • Fatty acids are converted to fatty acyl-CoA. This is distinct from acetyl-CoA.
   • This activation step uses 2 ATP equivalents.
   • This process is similar to TAG synthesis.
   • Short fatty acids (<12 carbons) can diffuse across the mitochondrial membranes.
   • Longer fatty acids require the carnitine shuttle for transport.
   • Carnitine deficiency can lead to issues with β-oxidation

4. Oxidation of Fatty Acids (β-oxidation)

   • Stage 1: Fatty acid chain is sequentially oxidized to produce 2-carbon acetyl-CoA units, NADH, and FADH2.

   • Stage 2: Oxidation of acetyl-CoA into $CO_2$ via the citric acid cycle, generating NADH and FADH2.

   • Stage 3: ATP is generated from NADH and FADH2 via the respiratory chain.

   • Each cycle generates acetyl-CoA and shortens the chain by 2 carbons.

   • FADH2 & NADH are also produced.

   • The cycle repeats.

   • β-oxidation of long chain and branched FA occurs in peroxisomes.

Regulation of Fatty Acid Oxidation

1. Release of FA from TAG: Regulated by HSL/ATGL and LPL.
2. FA Uptake: Regulated by FA transport proteins.
3. Entry of FA into Mitochondria: Regulated by the carnitine shuttle (regulated in response to nutritional state and energy demand).

The Carnitine Shuttle

The carnitine shuttle involves:

1. Carnitine acyltransferase 1 (CATI) - Located on the outer mitochondrial membrane, converts fatty acyl-CoA to fatty acyl-carnitine.
2. Carnitine transporter - Translocates fatty acyl-carnitine across the inner mitochondrial membrane.
3. Carnitine acyltransferase 2 (CATII) - Located on the inner mitochondrial membrane, converts fatty acyl-carnitine back to fatty acyl-CoA.
4. Malonyl-CoA regulates the carnitine shuttle.

Coordinated Regulation of Fatty Acid Oxidation and Biosynthesis

• Malonyl-CoA is the first intermediate in fatty acid synthesis and is synthesized by acetyl-CoA carboxylase (ACC), which is tightly regulated (Lecture 12).
• Increase/activation: FA Synthesis
• Decrease/inhibition: FA Oxidation
• This ensures fatty acid synthesis and oxidation are inversely regulated.

Acetyl-CoA Carboxylase Isoforms

• Muscle has a relatively low rate of FA synthesis but contains a significant concentration of malonyl-CoA due to an additional isoform of ACC, ACC2.
• ACC2 is also present in the liver and adipose tissue.
• ACC2 has similar regulation to ACC1 (phosphorylation, citrate).
• ACC2 has an additional 114 amino acid sequence at the N-terminus.

ACC2 Location and Function

• ACC2 knockout mice are resistant to diet-induced obesity.
• Lack of ACC2 leads to no Malonyl-CoA production at the mitochondrial membrane causing CATI to not be inhibited. Fatty acids transported into mitochondria and oxidized instead of stored as fat.

Ketone Bodies

• An alternative route for FA catabolism.
• Entry of acetyl-CoA into the citric acid cycle requires oxaloacetate (OAA).
• OAA is produced from pyruvate.
• When oxaloacetate is depleted, acetyl-CoA accumulates in the mitochondrial matrix and is converted into ketone bodies.
• Occurs at a low rate in well-nourished individuals, primarily in the liver.

Formation of Ketone Bodies from Acetyl-CoA

• Three acetyl-CoA molecules condense to produce HMG-CoA, releasing CoA.
• HMG-CoA is converted to acetoacetate in the mitochondria.
• HMG-CoA in the cytosol is used for cholesterol synthesis.
• Acetoacetate enters bloodstream.
• Acetone is exhaled as a gas.
• Acetoacetate and β-hydroxybutyrate are transported to extrahepatic tissues (e.g., the brain) for energy production.

Ketone Body Formation and Export from the Liver Occurs When:

• β-oxidation of FA is high (lots of acetyl-CoA produced).
• Glucose availability/utilisation is low (OAA levels fall).
• Conditions that promote gluconeogenesis (untreated diabetes, starvation).
• Exported from the liver for use by other tissues.

Ketone Bodies as Fuel

• Taken up and used as fuel by extrahepatic tissues (brain, heart, skeletal muscle, kidney).
• Water-soluble FA-derived fuel.
• The liver does not contain CoA transferase.

Importance of Ketone Synthesis

• Used by tissues that would usually oxidize glucose: spares glucose.
• Decreases the need for gluconeogenesis: spares muscle protein.
• Frees CoA from acetyl-CoA so fatty acid oxidation can continue.
• Some tissues (heart) get much of their energy from ketone bodies; others (brain) only use ketone bodies when glucose is not available.

Diabetic Ketoacidosis

• Untreated diabetes: lack of insulin/insulin resistance leads to the release of fatty acids from adipose tissue stores causing circulating FA, leading to β-oxidation along with Gluconeogenesis decreasing OAA, leading to acetyl-CoA, leading to ketone body synthesis.
• Plasma concentration: 25-30mM.
• Ketone bodies are acids (pKA~3.5).
• Impairs the ability of hemoglobin to bind oxygen.

Ketone Bodies During Starvation

• Carbohydrate stores are used rapidly, blood glucose falls.
• Insulin decreases and glucagon increases.
• Lipolysis increases, FA levels rise, FA oxidation increases, gluconeogenesis increases.
• Ketone bodies continue to rise.

Ketogenic Diets

• Low carbohydrate, high fat/protein.
• Carbohydrate shortage leads to low insulin, which induces ketosis.
• Potentially life-threatening acidosis.
• Can cause bad breath and high cholesterol.
• Possible effects with alcohol consumption.
• Possible therapeutic benefit (e.g., cancer).

Summary

• FA oxidation produces acetyl-CoA, a key metabolic intermediate that enters the citric acid cycle.
• A key control point is the transport of FA into mitochondria.
• CATI, a component of the transport system, is inhibited by malonyl-CoA.
• This ensures inverse regulation of FA synthesis and oxidation.
• ACC2 plays a key role in regulating FA oxidation.
• Acetyl-CoA produced from fatty acid oxidation can be converted to ketone bodies.
• Ketone bodies are produced by the liver and used as fuel by other tissues (heart, skeletal muscle, brain, kidney).
• This is an important adaptive mechanism but dangerous if uncontrolled.
• Increased under conditions that promote gluconeogenesis (untreated diabetes, starvation).