Lecture 14: Fatty Acid Catabolism

Overview

• Fats as Energy

• β-Oxidation

• Fatty Acid Regulation

• Ketone Bodies

Fats as Energy

• Dietary triacylglycerols provide about one-third of energy needs.

• Approximately 80% of the energy for mammalian heart and liver is derived from fatty acid oxidation.

• Hibernating animals, such as grizzly bears, predominantly utilize fats for energy.

• Glucose and glycogen supply quick, short-term energy; fats are more suited for long-term energy (months) storage.

• Fatty acids yield more energy per carbon due to their more reduced state and carry less water due to being nonpolar.

Fatty Acid Absorption

• Fats are emulsified by bile salts from the liver, stored in the gallbladder.

Lipid Transport

• Lipids are transported in chylomicrons to adipocytes.

• Released fatty acids bind to albumin (amphipathic) for delivery to other tissues.

Fat Storage

• Fat is stored in adipocytes as:

  • White fat: found in subcutaneous and visceral regions.

  • Beige fat: derived from white fat, activated by low temperatures or exercise.

  • Brown fat: derived from muscle cells, mainly around vital organs, contributes to thermogenesis.

• Adipocytes release adipokines to communicate with other body organs.

Fat Release

• Lipolysis is stimulated by glucagon and inhibited by insulin.

• Lipases hydrolyze triacylglycerols into free fatty acids and glycerol, a process regulated by hormones such as epinephrine and glucagon.

• Hydrolysis occurs within the cytoplasm of adipocytes.

Glycerol Enters Glycolysis

• Glycerol can be converted to glycolysis after being activated by glycerol kinase.

• Produces 21 ATP (20 net), allowing limited anaerobic metabolism from fats.

Fatty Acid Transport

• Fatty acids converted to fatty acyl-CoA either in endoplasmic reticulum or outer mitochondria; this is required for further transport and β-oxidation.

• Small fatty acids (<12 carbons) can diffuse freely into mitochondrial membranes.

• Larger fatty acyl-CoAs are transported into the matrix using the carnitine shuttle, facilitated by CAT I and CAT II enzymes.

Fatty Acid Oxidation

• Occurs in the mitochondrial matrix, consisting of three stages:

  1. β-Oxidation: converts fatty acid into acetyl-CoA while producing NADH and FADH2.

  2. Citric Acid Cycle: oxidizes acetyl-CoA to CO2, producing more NADH and FADH2.

  3. Oxidative Phosphorylation: generates ATP from NADH and FADH2.

The β-Oxidation Pathway

• For palmitoyl-CoA (C16), the pathway involves 7 rounds of oxidation resulting in 8 acetyl-CoA.

Steps of β-Oxidation

1. Dehydrogenation: Converts an alkane to an alkene using acyl-CoA dehydrogenase.

2. Hydration: Alkene is hydrated to form an alcohol by enoyl-CoA hydratase.

3. Dehydrogenation: Alcohol is converted to a ketone by β-hydroxyacyl-CoA dehydrogenase.

4. Chain Transfer: Fatty acid chain is transferred to a new CoA molecule via acyl-CoA acetyltransferase.

Trifunctional Protein

• Catalyzes steps 2-4 and processes longer fatty acid chains.

• Contains both hydratase and thiolase activities, enabling efficient substrate channeling.

Summary of Fatty Acid Catabolism

• For palmitate (C16):

  • Produces 8 acetyl-CoA, 7 NADH, and 7 FADH2 from complete β-oxidation.

  • Each acetyl-CoA further oxidizes in the citric acid cycle, leading to a total of 108 ATP.

Conserved Pathways

• β-Oxidation is a conserved reaction sequence that modifies β-carbons.

Unsaturated Fatty Acids

• Monounsaturated fatty acids require an isomerase for β-oxidation.

• Polyunsaturated fatty acids need both an isomerase and a reductase for breakdown.

Odd-Numbered Fatty Acids

• Odd-numbered fatty acids yield propionyl-CoA during β-oxidation, which can participate in gluconeogenesis.

Coenzyme B12

• Necessary for the breakdown of odd-numbered fatty acids and plays a key role in red blood cell production.

• Vitamin B12 deficiency can lead to pernicious anemia.

Fatty Acid Regulation

• Insulin activates fatty acid synthesis while glucagon triggers fatty acid breakdown.

β-Oxidation Location

• In animals, takes place in mitochondria; peroxisomes used for processing very long-chain fats.

• In plants, peroxisomal or glyoxysomal pathways serve similar functions.

Ketone Bodies

• Formed from acetyl-CoA during periods of low glucose via ketogenesis in the liver.

• Ketone bodies (acetone, acetoacetate, β-hydroxybutyrate) are utilized by various tissues for energy.

Ketone Production

• Increased during starvation and diabetes due to low oxaloacetate and high acetyl-CoA; can lead to ketoacidosis if levels rise excessively.

Ketones and the Brain

• The brain has limited ability to utilize fatty acids and relies on glucose or ketones for energy.

• Ketones are vital as alternative energy sources during glucose shortages.