Fatty Acid Metabolism and Transport

Fatty Acid Catabolism

• Fats are esters of glycerol with fatty acids.
• Fats are highly reduced, similar to hydrocarbons, providing high energy.
• In the liver and heart, fats provide ~80% of the total energy.
• Fats are hydrophobic and segregate from water, thus easy to store as lipid droplets.
• Fats do not raise the osmolarity of the cell, allowing storage in large amounts.
• Fats are a 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 intestinal mucosa and converted to triacylglycerols.
• Chylomicrons transport triacylglycerols with cholesterol and apolipoproteins to tissues.
• Lipoprotein lipase converts triacylglycerols to fatty acids and glycerol.

Structure of Chylomicrons

• Chylomicrons are 100-500 nm in size.
• Major components are: triacylglycerols (80%), phospholipids, cholesterol, cholesterol esters, and apolipoproteins (lipid-binding proteins).
• Various lipid-protein combinations like chylomicrons, VLDL, and VHDL exist.
• Apolipoprotein moieties are recognized by cell surface receptors.

Mobilization of Triacylglycerols Stored in Adipose Tissue

• Epinephrine binding to adipocyte receptors activates adenylyl cyclase, producing cAMP.
• cAMP activates protein kinase A (PKA).
• PKA phosphorylates perilipin, 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 to muscles for energy generation.

Metabolism of Glycerol

• Glycerol accounts for ~5% of total fat energy.
• Energy is harvested through glycerol kinase converts glycerol to glycerol 3 phosphate through normal glycolysis.
• Phosphorylated species are negatively charged, and trapped inside the cytoplasm.

Fatty Acid "Activation" Prior to Oxidation

• Fatty acid oxidation enzymes are located in the mitochondrial matrix.
• Fatty acids must be conjugated with CoA before entering mitochondria.
• Conjugation is highly exothermic, releasing pyrophosphate, which is further hydrolyzed to two molecules of phosphate.

Fatty Acid Transport into Mitochondria

• Carnitine shuttles fatty acids between cytosol and mitochondria.
• Fatty acids are converted to carnitine esters, committing them to mitochondrial oxidation.

Oxidation of Fatty Acids

• In humans, fatty acid beta-oxidation primarily occurs in the mitochondria.
• Fatty acid beta-oxidation proceeds in three sequential stages:
  • Stage 1: sequential beta-oxidation rounds to generate acetyl CoA.
  • Stage 2: oxidation of acetyl CoA to CO2, FADH2, NADH using the citric acid cycle.
  • Stage 3: transfer of electrons from FADH2, NADH to O2, generating ATP.

Stage 1: Beta-Oxidation of Saturated Fatty Acids

• Acyl-CoA dehydrogenase catalyzes the first step.
• Enoyl-CoA hydratase converts cis to trans.
• Beta-hydroxyacyl-CoA dehydrogenase oxidizes the hydroxyl group.
• Acyl-CoA acetyltransferase (thiolase) cleaves off an acetyl-CoA.

Beta-Oxidation of Saturated Fatty Acids: Energy Balance

• Complete energy yield from palmitic (C16) acid to acetyl-CoA is 129 ATP.
• The procedure is for even numbered saturated fatty acids.

Monounsaturated Fatty Acid Oxidation

• Monounsaturated fatty acids have a cis double bond.
• Enoyl-CoA isomerase converts cis to trans, allowing further beta-oxidation.

Polyunsaturated Fatty Acid Oxidation

• Polyunsaturated fatty acids have multiple double bonds.
• Two additional enzymes (isomerase and reductase) are required for proper beta-oxidation, due to the cis double bonds.
• This method yields less energy compared to saturated fatty acids due to reduced reduced products.

Mono/Polyunsaturated Fatty Acid Oxidation: Summary

• Most unsaturated fatty acids have the cis configuration.
• This presents issues with beta-oxidation.
• An intermediate with a double bond between C-3 and C-4 is produced.
• The intermediate requires isomerase for proper enoyl-CoA hydratase function.
• If the cis bond is between C-4 and C-5, a reductase reduces the 2,4 bond followed by an isomerase.
• There are two additional enzymes for handling the configurations during beta oxidation.
• Less total energy output compared to saturated fatty acids due to reductase utilizing NADPH.

Oxidation of Odd-Number Fatty Acids

• Odd-number fatty acids yield propionyl-CoA after beta-oxidation.
• Propionyl-CoA is converted to succinyl-CoA.
• The intermediate C3 fragment is utilized for the generation succinyl-CoA.
• Coenzyme B12 is required for the conversion step.

Regulation of Fatty Acid Oxidation

• High glucose levels stimulate the enzyme that synthesizes fatty acid precursor malonyl-CoA.
• Malonyl-CoA inhibits beta-oxidation by blocking fatty acid transport into mitochondria.

Ketone Bodies—Alternative Fuel to Sugars

• Acetyl-CoA from fatty acid oxidation can become ketone bodies.
• Acetoacetate, acetone, and beta-hydroxybutyrate are ketone bodies (acids).
• The accumulation of ketone bodies results in ketoacidosis.
• Ketone bodies are generated in the liver and exported as an energy source to muscle, renal cortex, and brain during periods of low or no glucose availability.

Ketone Bodies—Summary

• Liver acetyl-CoA from beta-oxidation can enter the TCA cycle or form ketone bodies.
• The path depends on oxaloacetate levels (OAA) in the liver.
• Low OAA levels force acetyl-CoA into ketone body production, providing an alternative energy source for tissues in cases of low glucose.
• Diabetic ketosis is a result of insufficient insulin that causes low glucose uptake by cells which stimulates glucagon, therefore increasing ketone body production.

Drugs and Diseases

• Diseases include diabetes and diabetic ketoacidosis.
• Drugs and vitamins include epinephrine and vitamin B12.
• Blood components to analyze include chylomicrons, VLDL, LDL, HDL, and ketone bodies.

This quiz covers the processes of fatty acid catabolism, digestion, and the structure and function of chylomicrons. Explore the significance of fats as energy sources and their unique properties in the body. Test your knowledge on how fats are processed and transported within the body.