Fatty Acid Catabolism Overview

Fatty Acid Catabolism Overview

• Fats are esters of glycerol and fatty acids.
• Fats are highly reduced, thus have high energy content (~80% of total energy for liver and heart).
• Fats are hydrophobic and inert, segregating from water; easy to store as lipid droplets without raising osmolarity.
• 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 taken up by intestinal mucosa and converted to triacylglycerols.
• Chylomicrons are formed, encapsulating triacylglycerols with cholesterol and apolipoproteins.
• Chylomicrons transport fats through the lymphatic system and bloodstream to tissues.
• Lipoprotein lipase converts triacylglycerols in chylomicrons to fatty acids and glycerol, releasing them into cells.

Structure of Chylomicrons

• Chylomicrons are 100-500 nm in size.
• Chylomicrons primarily consist of triacylglycerols (~80%), phospholipids, cholesterol, cholesterol esters, and apolipoproteins (lipid-binding proteins).
• Different combinations of lipids and proteins create various lipoprotein types, including chylomicrons, VLDL, and HDL.

Mobilization of Triacylglycerols in Adipose Tissue

• Binding of epinephrine to adipocyte receptors stimulates adenylyl cyclase.
• cAMP activates protein kinase A (PKA).
• PKA phosphorylates perilipin, exposing triacylglycerols to hormone-sensitive lipase (HSL).
• HSL hydrolyzes triacylglycerols into fatty acids and glycerol.
• Fatty acids are released and transported by serum albumin to other tissues for energy generation.

Metabolism of Glycerol

• Glycerol accounts for ~5% of total fat energy.
• Glycerol is converted to glyceraldehyde 3-phosphate, entering the glycolytic pathway.
• All phosphorylated species are negatively charged, trapping them in the cytoplasm.

Fatty Acid Activation Prior to Oxidation

• Fatty acid oxidation enzymes are in mitochondrial matrix.
• Fatty acids must be transported from the cytoplasm to mitochondria and conjugated with CoA.
• This conjugation is highly exothermic, releasing pyrophosphate, which is further hydrolyzed into two phosphates.

Fatty Acid Transport into Mitochondria

• Carnitine acts as a fatty acid shuttle between cytosol and the mitochondrial matrix.
• Fatty acyl-CoA is converted to fatty acylcarnitine by carnitine acyltransferase I.
• Fatty acylcarnitine crosses the inner mitochondrial membrane.
• Fatty acylcarnitine is converted back to fatty acyl-CoA by carnitine acyltransferase II.

Oxidation of Fatty Acids

• Fatty acid oxidation (β-oxidation) occurs primarily in mitochondria.
• It involves sequential cycles of oxidation.
• Each cycle shortens the fatty acid chain by two carbons, producing one acetyl-CoA, one FADH2, and one NADH.
• Acetyl-CoA enters the citric acid cycle.
• FADH2 and NADH contribute electrons to the electron transport chain, generating ATP.

Stage 1: β-Oxidation of Saturated Fatty Acids

• Acyl-CoA dehydrogenase oxidizes the fatty acyl-CoA, producing trans-Δ2-enoyl-CoA.
• Enoyl-CoA hydratase adds water to the double bond.
• β-hydroxyacyl-CoA dehydrogenase oxidizes the hydroxyl group, producing β-ketoacyl-CoA.
• β-ketoacyl-CoA thiolase cleaves off a two-carbon acetyl-CoA fragment, regenerating the fatty acyl-CoA for the next cycle.

β-Oxidation of Saturated Fatty Acids: Energy Balance

• Complete energy yield from palmitic acid (16 carbons) to acetyl-CoA is ~129 ATP.
• Calculation involves ATP produced from NADH, FADH2, and acetyl-CoA oxidation in the citric acid cycle.

Monounsaturated Fatty Acid Oxidation

• Monounsaturated fatty acids have a cis double bond, requiring an enoyl-CoA isomerase.
• This intermediate isomerase is required to produce trans-Δ2-enoyl-CoA.
• The remaining steps of β-oxidation are similar to those of saturated fatty acids.

Polyunsaturated Fatty Acid Oxidation

• Polyunsaturated fatty acids have more than one double bond.
• 2,4-dienoyl-CoA reductase and enoyl-CoA isomerase are required to correctly position the double bonds.
• The further oxidation process is similar to those in other fatty acid oxidation.

Mono/Polyunsaturated Fatty Acid Oxidation Summary

• Most naturally occurring unsaturated fatty acids have the cis configuration.
• Intermediate products require isomerases and reductases for normal β-oxidation due to the correct positioning of the double bonds.
• These additional steps lead to less energy production.

Oxidation of Odd-Number Fatty Acids

• Odd-number fatty acids produce propionyl-CoA at the final cycle.
• Propionyl-CoA is converted to succinyl-CoA.
• Succinyl-CoA enters the citric acid cycle.

Ketone Bodies - Alternative Fuel to Sugars

• Acetyl-CoA, produced from fatty acid oxidation, can be converted to ketone bodies (acetoacetate, acetone, β-hydroxybutyrate) in the liver.
• These ketone bodies are exported to other tissues (e.g., heart, muscle, brain) as an alternative fuel source during conditions with low glucose.

Ketone Bodies Formation

• Starvation and uncontrolled diabetes cause excess ketone body production.
• The liver synthesizes ketone bodies from acetyl-CoA when glucose is low.
• Ketone bodies are transported to other tissues for energy.

Regulation of Fatty Acid Oxidation

• High glucose levels stimulate malonyl-CoA production, inhibiting fatty acid transport into mitochondria.
• Insulin increases fatty acid synthesis and inhibits breakdown.
• Glucagon promotes fatty acid mobilization and inhibits synthesis.
• Malonyl-CoA blocks fatty acid transport into mitochondria, regulating fatty acid oxidation.

Drugs and Diseases

• Diseases like diabetes can lead to diabetic ketoacidosis (high ketone bodies in the blood).
• Hormones (e.g., epinephrine) and vitamins (e.g., vitamin B12) are involved in metabolic processes.
• Monitoring metabolites (like chylomicrons, VLDL, LDL, HDL, and ketone bodies) helps assess metabolic function.

Explore the biochemical processes involved in fatty acid catabolism and fat digestion. This quiz covers the roles of bile salts, intestinal lipases, and chylomicrons in fat metabolism. Understand how fats serve as an energy source for various organisms.