Fatty Acid Catabolism Overview

Fatty Acid Catabolism

• Fats are esters of glycerol with fatty acids.
• Highly reduced structures, similar to hydrocarbons, have high energy per gram.
• In the liver and heart, fats provide approximately 80% of the total energy consumed.
• Fats are hydrophobic and inert, segregating from water.
• They are easy to store as lipid droplets without raising the osmolarity of the cell.
• Fats can be stored in large amounts in cells without risk of undesired chemical reactions.
• Fats are the sole energy source for hibernating animals and migratory birds.

Digestion, Mobilization, and Transport of Fats

• Bile salts emulsify dietary fats in the small intestine, forming mixed micelles.
• Intestinal lipases degrade triacylglycerols.
• Fatty acids and other breakdown products are absorbed by the intestinal mucosa and converted into triacylglycerols.
• Triacylglycerols are incorporated with cholesterol and apolipoproteins into chylomicrons.
• Chylomicrons move through the lymphatic system and bloodstream to tissues.
• Lipoprotein lipase converts triacylglycerols to fatty acids and glycerol in capillaries.
• Fatty acids enter cells.

Structure of Chylomicrons

• Size: 100-500 nm.
• Composition: triacylglycerols (80%), phospholipids, cholesterol, and cholesterol esters, apolipoproteins (lipid-binding proteins).
• Various combinations of lipids and proteins (e.g., chylomicrons, VLDL, VHDL) are distinguished.
• Protein moieties of lipoproteins are recognized by receptors on cell surfaces.

Mobilization of Triacylglycerols Stored in Adipose Tissue

• Binding of epinephrine to receptors on adipocytes stimulates adenylyl cyclase.
• cAMP produced activates protein kinase A (PKA).
• PKA phosphorylates perilipin on the surface of lipid droplets, making fats accessible to hormone-sensitive lipase (HSL).
• HSL hydrolyzes triglycerides into fatty acids and glycerol.
• Fatty acids leave adipocytes and are transported by serum proteins (e.g., albumin) to muscles for energy generation.

Metabolism of Glycerol

• Glycerol accounts for approximately 5% of the total energy of fats.
• Energy is harvested through conversion into glyceraldehyde 3-phosphate, then via the glycolytic pathway.
• All phosphorylated species are negatively charged and trapped into the cytoplasm.

Fatty Acid "Activation" Prior to Oxidation

• Enzymes for fatty acid oxidation are located in the mitochondrial matrix.
• Fatty acids must be conjugated with CoA in the cytoplasm before transport to mitochondria.
• Conjugation is highly exergonic due to pyrophosphate release, further hydrolyzed to two phosphates.

Fatty Acid Transport into Mitochondria

• Carnitine acts as a fatty acid shuttle between the cytosol and the interior of mitochondria.
• Fatty acid is converted to a carnitine ester to be transported into mitochondria.

Oxidation of Fatty Acids

• In humans, β-oxidation primarily occurs in mitochondria.
• It comprises three stages:
  • Sequential β-oxidation rounds to generate acetyl-CoA.
  • Oxidation of acetyl-CoA to CO2, FADH2, and NADH using the citric acid cycle.
  • Transfer of electrons from FADH2 and NADH to O2, with ATP generation.

Stage 1: β-Oxidation of Saturated Fatty Acids

• Acyl-CoA dehydrogenase removes hydrogens to produce FADH2.
• Enoyl-CoA hydratase adds water, creating a hydroxyl group.
• β-hydroxyacyl-CoA dehydrogenase oxidizes the hydroxyl group, forming a ketone.
• β-ketoacyl-CoA thiolase cleaves off an acetyl group, repeating the cycle.
• This cycle continues until the entire fatty acid is oxidized into acetyl-CoA's.

Oxidation of Odd-Number Fatty Acids

• Odd-number fatty acids yield propionyl-CoA at the end of β-oxidation.
• Propionyl-CoA must be converted to succinyl-CoA, an intermediate in the citric acid cycle, before entering the TCA cycle.
• B12 is used for isomerization of methylmalonyl-CoA to succinyl-CoA

Monounsaturated Fatty Acid Oxidation

• Requires an additional isomerase enzyme to convert the cis bond to a trans bond.
• An additional reductase is needed as well.

Polyunsaturated Fatty Acid Oxidation

• Contains two or more double bonds.
• Requires additional enzymes (isomerase, reductase).
• Less energy is produced compared to saturated fatty acids due to the need for additional enzymes.

Mono/polyunsaturated Fatty Acid Oxidation: Summary

• Most naturally occurring unsaturated fatty acids have a cis conformation.
• This causes issues with β-oxidation due to the need for additional enzymes.

Regulation of Fatty Acid Oxidation

• High glucose levels stimulate the synthesis of malonyl-CoA.
• Malonyl-CoA inhibits the transport of fatty acids into mitochondria, thus regulating fatty acid oxidation.

Ketone Bodies - Alternative Fuel to Sugars

• Acetyl-CoA produced from fatty acid oxidation can be converted into ketone bodies.
• Acetoacetate, acetone, and β-hydroxybutyrate are ketone bodies.
• Ketone bodies can be used as fuel by other tissues when glucose is unavailable.

Ketone Bodies Formation and Export from the Liver

• Starvation and untreated diabetes lead to overproduction of ketone bodies.
• Hepatocytes synthesize ketone bodies from acetyl-CoA.
• Ketone bodies are exported to peripheral tissues for use.

Drugs and Diseases

• Diseases and conditions related to fatty acid metabolism, such as diabetes and diabetic ketoacidosis are discussed.
• Drugs and vitamins related to these conditions, like epinephrine, B12, and hydroxocobalamin.
• Metabolites and blood components that are analyzed in connection to these imbalances.