Lipid Catabolism

Lipid Catabolism

• Overview

  • Lipid catabolism is the metabolic process by which lipids (fats) are broken down.

  • Daily intake: Approximately 60-150 g of lipids/day; about 90% of which are triacylglycerols (TAGs).

Components of Lipid Catabolism

• Key Substrates and Products

  • Glycerol

  • Fatty Acids

  • Acetyl CoA

  • Dihydroxyacetone phosphate (DHAP)

  • Glyceraldehyde 3-phosphate

  • Pyruvic Acid

  • Krebs Cycle

• Enzymes Involved

  • Lipase: Enzymes responsible for hydrolyzing lipids.

Digestion, Absorption, and Transport of Lipids

• Stages of Lipid Breakdown

  1. Mouth

  • Medium-chain TAGs are hydrolyzed by lipases, producing free fatty acids and diacylglycerols (DAGs).

  1. Stomach

  • Partial digestion occurs by gastric lipase.

  1. Small Intestine

  • Dietary lipids are emulsified by bile salts.

  • Emulsified fats are hydrolyzed by pancreatic lipases.

  • Reaction:

    • $( ext{Pancreatic lipase: } R₁C-O-C(R₂)H<em>2 + H</em>2O)$

      • Results in the formation of 2 fatty acids from the TAGs.

Control of Lipid Digestion

• Hormonal Regulation

  • Cholecystokinin (CCK): Triggered by dietary lipids in the blood, leading to gallbladder contraction and bile release.

  • Secretin: Released in response to acidic chyme, it neutralizes intestinal contents and increases bicarbonate and enzyme secretion from pancreas.

• Key Organs Involved

  • Liver

  • Gallbladder

  • Pancreas

Transport Mechanisms

• Chylomicrons: Lipoproteins that transport dietary lipids.

  • Components of chylomicrons include:

  • Apoproteins (e.g., B-48, C-I, C-II)

  • Phospholipids

  • Cholesterol

  • TAGs

• Pathway to Tissues

  • Process takes lipids from the intestinal lumen through mucosal cells to the bloodstream and then to adipose tissues or muscles.

Storage of Lipids

• Lipids are stored as triacylglycerols in adipose tissues.

  • Highly concentrated energy stores in the cytoplasm of adipose cells.

  • A typical 70-kg man has:

  • ~600 kcal worth of glycogen

  • ~100,000 kcal worth of TAGs.

Utilization of Dietary Lipids by Tissues

• Lipid Mobilization: TAGs in adipose tissues are hydrolyzed to fatty acids and glycerol, then transported to energy-requiring tissues.

• Fatty Acid Activation and Transport: Fatty acids react with CoA to form fatty acyl CoA, allowing entry into mitochondria for oxidation.

β-Oxidation of Fatty Acyl CoA

• Overview of Process

  • Converts each 2 carbon units of fatty acid into Acetyl CoA.

  • Each cycle generates 1 FADH2 and 1 NADH.

• Stages of β-Oxidation

  1. Oxidation

  • Catalyzed by Acyl CoA dehydrogenase:
    $( ext{Fatty acyl-CoA} + FAD → ext{trans-A²-Enoyl CoA} + FADH_2)$

  1. Hydration

  • Catalyzed by Enoyl hydratase:
    $( ext{trans-A²-Enoyl CoA} + H_2O <br>ightarrow ext{L-3-Hydroxyacyl CoA})$

  1. Second Oxidation

  • Catalyzed by Hydroxy acyl CoA dehydrogenase:
    $( ext{L-3-Hydroxyacyl CoA} + NAD^+ <br>ightarrow 3-Ketoacyl CoA + NADH + H^+)$

  1. Thiolyisis

  • Release of Acetyl CoA:
    $( ext{3-Ketoacyl CoA} + CoA → ext{Fatty acyl-CoA (shortened by 2 carbon atoms)} + ext{Acetyl CoA})$

• Cycle of β-Oxidation

  • The length of the fatty acid determines:

  • Number of oxidations = $ext{number of Carbons/2 - 1}$

  • Number of acetyl CoA = $ext{number of Carbons/2}$

Ketogenesis

• Formation of Ketone Bodies

  • Occurs in liver mitochondria during:

  • Starvation with low glucose levels.

  • High fat and low carbohydrate diets.

  • Diabetic conditions.

• Key Components

  • Acetyl CoA is converted into ketone bodies:

  • Acetoacetate

  • β-Hydroxybutyrate

  • Acetone

• Transport and Usage

  • Ketone bodies can be transported to peripheral tissues such as:

  • Skeletal and cardiac muscle

  • Brain under extreme glucose deficiency.

Summary of Energy Yield from Fatty Acid Oxidation

• ATP Yield Calculation

  • For Palmitoyl CoA:

  • 8 Acetyl CoA produced,

  • 7 FADH2 and 7 NADH generated.

  • Total ATP produced can be derived from each NADH and FADH2 based on their energetic yield during oxidative phosphorylation.

LIPID CATABOLISM

Comprehensive Reviewer

Including Enzyme Reactions, Formulas, and Metabolic Pathways

Chapter 1: Introduction to Lipid Catabolism

Overview

• Lipid catabolism refers to the breaking down of lipids (fats) to generate energy (ATP) and provide carbon skeletons for other metabolic pathways

• Nearly 90% of dietary lipids are triacylglycerols (TAGs)

• Daily lipid intake: ~60–150 grams/day

• Lipids provide 9 kcal/gram (more than 2× carbohydrates or proteins at 4 kcal/gram)

Key Lipid Types in Catabolism

• Triacylglycerols (TAGs): Three fatty acids esterified to glycerol

• Phospholipids (PLs): Glycerol backbone with 2 fatty acids and a phosphate group

• Cholesteryl esters (CEs): Cholesterol with an esterified fatty acid

Chapter 2: Digestion, Absorption and Transport

Four-Step Process

1. Mouth: Lingual lipase breaks down medium-chain TAGs to free fatty acids (FAs) and diacylglycerols (DAGs)

2. Stomach: Gastric lipase provides partial digestion

3. Small Intestine: Main site of lipid digestion and absorption

• Bile salts emulsify dietary lipids, increasing surface area

• Pancreatic lipase hydrolyzes TAGs to 2-monoacylglycerols (2-MAGs) and FAs

4. Transport to Adipose/Muscle: Absorbed FAs and MAGs are packaged into chylomicrons

Control of Lipid Digestion

• Cholecystokinin (CCK): Hormone released from small intestine in response to dietary lipids

  • Stimulates gallbladder contraction and bile release

  • Stimulates pancreatic enzyme secretion

• Secretin: Released in response to acidic chyme

  • Stimulates pancreas to release bicarbonate-rich solution to neutralize pH

• Chylomicrons

  • Lipoprotein particles composed of: TAGs (~85%), phospholipids, cholesterol, and proteins (apolipoproteins)

• Synthesized in intestinal mucosal cells

• Transported via lymphatic system to bloodstream

• Primary carriers of exogenous dietary lipids

Chapter 3: Three Stages of Fatty Acid Utilization

Stage 1: Lipid Mobilization

• Occurs in adipose tissue during energy demand

• TAGs in adipose tissue are broken down to FAs and glycerol

• FAs are transported in blood bound to serum albumin

Key Enzymes - Stage 1

Stage 2: Fatty Acid Activation and Transport to Mitochondrion

• Occurs in cytosol and mitochondrial membrane

• FAs must be activated and transported into mitochondrial matrix for β-oxidation

• Carnitine shuttle system transports fatty acyl-CoA across inner mitochondrial membrane

Key Enzymes - Stage 2

Stage 3: β-Oxidation of Fatty Acyl-CoA

• Occurs in mitochondrial matrix

• Removes 2-carbon units (as acetyl-CoA) sequentially from the carboxyl end of FA

• Generates 1 FADH₂ and 1 NADH per cycle

• Consists of 4 repeating reactions

Four Steps of β-Oxidation

Step 1: Oxidation (Dehydrogenation)

Step 2: Hydration

Step 3: Oxidation (Dehydrogenation)

Step 4: Thiolysis (Release of Acetyl-CoA)

β-Oxidation of Palmitoyl-CoA (C16, saturated)

• Overall equation:

Palmitoyl-CoA + 7 FAD + 7 NAD⁺ + 7 CoA + 7 H₂O → 8 Acetyl-CoA + 7 FADH₂ + 7 NADH + 7 H⁺

• Number of cycles = (carbon atoms / 2) – 1 = (16 / 2) – 1 = 7

• Acetyl-CoA produced = carbon atoms / 2 = 16 / 2 = 8

Chapter 4: Glycerol Metabolism

• Glycerol is released during TAG breakdown

• Cannot be metabolized by adipose tissue (lacks glycerol kinase)

• Transported to liver for metabolism

Glycerol → DHAP Pathway (Liver)

• DHAP enters glycolysis as the triose phosphate intermediate

• Can be used for ATP generation, gluconeogenesis, or lipogenesis

Chapter 5: Ketogenesis

• Formation of ketone bodies from excess acetyl-CoA

• Occurs in liver mitochondria

• Triggered during: starvation, high-fat/low-carbohydrate diet, or diabetic conditions

Ketone Body Formation Pathway

The Three Ketone Bodies

1. Acetoacetate: First ketone body formed; has a ketone group; can be reduced to β-hydroxybutyrate

2. β-Hydroxybutyrate (D-form): Most abundant ketone body; primary energy substrate

3. Acetone: Volatile ketone; forms non-enzymatically; excreted via lungs (fruity odor in breath)

Ketone Body Utilization

• Tissues that use ketones: Skeletal muscle, cardiac muscle, kidneys, and brain

• Brain: Uses ketones only under extreme glucose deficiency (during prolonged starvation)

• Livers cannot use ketones: Lack thiophorase enzyme needed to activate ketones

• Conversion to Acetyl-CoA: Enters citric acid cycle for ATP production

Key Definitions

Review Questions

1. What is the typical daily intake of lipids, and what percentage is made up by triacylglycerols?

2. Name the three main locations of lipid digestion and the key processes that occur in each.

3. Explain the role of cholecystokinin (CCK) and secretin in lipid digestion control.

4. What is the composition of a chylomicron, and why is it important for lipid transport?

5. Describe the carnitine shuttle system and why it is essential for β-oxidation.

6. Write the complete equation for the activation of a fatty acid to fatty acyl-CoA.

7. What are the four steps of β-oxidation, and which enzymes catalyze each step?

8. Calculate how many cycles of β-oxidation are needed for complete oxidation of a 16-carbon saturated fatty acid.

9. How much ATP is generated from the complete β-oxidation of one molecule of palmitate (C16)?

10. Explain the conversion of glycerol to DHAP and its entry into glycolysis.

11. Under what physiological conditions is ketogenesis activated?

12. Name the three ketone bodies and describe their structural differences.

13. Which tissues can utilize ketone bodies, and which cannot?

14. Why does acetone have a fruity odor on the breath of diabetic patients in ketoacidosis?

15. How does CPT-I deficiency affect fatty acid oxidation?

Quick Reference Tables

Complete Enzyme Summary with Reaction Equations

Energy Yield from Palmitoyl-CoA Oxidation

Comparison: Lipids vs. Carbohydrates vs. Proteins