# Lecture 19: Fatty Acid Catabolism
## Biochemistry
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## Learning Objectives
By the end of this lecture, students will be able to:
1. Describe the mobilization of fatty acids from adipose tissue
2. Explain the activation of fatty acids and the role of the carnitine shuttle
3. Describe the four reactions of beta-oxidation and its products
4. Calculate the ATP yield from complete oxidation of a fatty acid
5. Describe the oxidation of unsaturated and odd-chain fatty acids
6. Explain ketone body synthesis, utilization, and clinical significance
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## Lecture Content
### I. Mobilization of Fatty Acids
Triglycerides stored in adipose tissue represent the body's largest energy reserve, containing approximately 100,000 kcal compared to approximately 1,600 kcal for glycogen. During fasting, exercise, or stress, glucagon and epinephrine activate **hormone-sensitive lipase (HSL)** via the cAMP/PKA pathway. PKA phosphorylates both HSL (activating it) and perilipin (the coat protein on lipid droplets, granting HSL access to triglycerides). Adipose triglyceride lipase (ATGL) initiates the first step of lipolysis. HSL hydrolyzes triglycerides to free fatty acids and glycerol. **Insulin** opposes this process by activating a phosphatase that dephosphorylates HSL, promoting fat storage. Released free fatty acids bind to **albumin** for transport in the blood. Glycerol travels to the liver, where glycerol kinase converts it to glycerol-3-phosphate, then to DHAP, entering glycolysis or gluconeogenesis.
### II. Fatty Acid Activation
Before oxidation, fatty acids are activated to acyl-CoA by **acyl-CoA synthetase** (thiokinase) on the outer mitochondrial membrane: fatty acid + CoA + ATP yields acyl-CoA + AMP + PPi. Pyrophosphate hydrolysis drives the reaction forward, with a net cost of 2 ATP equivalents. Long-chain acyl-CoA cannot directly cross the inner mitochondrial membrane.
### III. The Carnitine Shuttle
Long-chain fatty acids (C12-C20) require the carnitine shuttle for transport into the mitochondrial matrix. **CPT-I** (carnitine palmitoyltransferase I) on the outer membrane converts acyl-CoA plus carnitine to acylcarnitine plus CoA. This is the **rate-limiting step** of fatty acid oxidation and is **inhibited by malonyl-CoA**, the first committed intermediate of fatty acid synthesis, ensuring that synthesis and oxidation do not occur simultaneously. **Carnitine-acylcarnitine translocase** in the inner membrane exchanges acylcarnitine (inward) for free carnitine (outward). **CPT-II** on the matrix side regenerates acyl-CoA from acylcarnitine. **Carnitine deficiency** causes impaired fatty acid oxidation, presenting with muscle weakness and hypoketotic hypoglycemia; it may be primary (genetic defect in the carnitine transporter) or secondary (from drugs like valproic acid or organic acidemias). Medium- and short-chain fatty acids can enter the matrix directly without carnitine.
A diagram of the carnitine shuttle system. The outer mitochondrial membrane, intermembrane space, and inner mitochondrial membrane are shown. Acyl-CoA synthetase on the outer membrane activates the fatty acid. CPT-I on the outer membrane converts acyl-CoA to acylcarnitine. The translocase in the inner membrane exchanges acylcarnitine for free carnitine. CPT-II on the matrix side regenerates acyl-CoA. Malonyl-CoA is shown as an inhibitor of CPT-I with a red inhibitory arrow. The fate of acyl-CoA in the matrix (entering beta-oxidation) is indicated.
### IV. Beta-Oxidation
Beta-oxidation occurs in the **mitochondrial matrix** as a repeating cycle of four reactions that removes 2-carbon units as acetyl-CoA. Each cycle produces 1 FADH2 + 1 NADH + 1 acetyl-CoA.
**Step 1 (Acyl-CoA Dehydrogenase)** oxidizes acyl-CoA using FAD to introduce a trans double bond between C2 and C3. Multiple isozymes exist for different chain lengths (VLCAD, LCAD, MCAD, SCAD). **MCAD deficiency** is the most common inherited defect of fatty acid oxidation, presenting with hypoketotic hypoglycemia, a Reye-like syndrome, and risk of sudden infant death. **Step 2 (Enoyl-CoA Hydratase)** hydrates the double bond to produce L-3-hydroxyacyl-CoA. **Step 3 (3-Hydroxyacyl-CoA Dehydrogenase)** oxidizes the hydroxyl to a keto group using NAD+. **Step 4 (Thiolase)** cleaves the 3-ketoacyl-CoA with CoA, releasing acetyl-CoA and a shortened acyl-CoA that re-enters the cycle.
### V. Energy Yield from Fatty Acid Oxidation
For palmitoyl-CoA (C16, saturated), 7 cycles of beta-oxidation produce 8 acetyl-CoA, 7 FADH2, and 7 NADH. The ATP yield is: 8 acetyl-CoA x 10 ATP = 80; 7 FADH2 x 1.5 = 10.5; 7 NADH x 2.5 = 17.5; subtotal 108; minus 2 for activation; **net 106 ATP per palmitate**. This high yield explains why fats produce approximately 9 kcal/g compared to approximately 4 kcal/g for carbohydrates.
### VI. Oxidation of Unsaturated Fatty Acids
Unsaturated fatty acids require additional enzymes. **Enoyl-CoA isomerase** converts cis-delta-3 double bonds to the trans-delta-2 configuration needed for step 1, as required for monounsaturated fatty acids like oleate. **2,4-Dienoyl-CoA reductase** (NADPH-dependent) reduces 2,4-dienoyl intermediates encountered with polyunsaturated fatty acids like linoleate. Unsaturated fatty acids yield slightly less ATP because one FADH2 is bypassed for each pre-existing double bond.
### VII. Oxidation of Odd-Chain Fatty Acids
Odd-chain fatty acids undergo normal beta-oxidation except for the final cycle, which produces **propionyl-CoA** (3C) instead of acetyl-CoA. Propionyl-CoA is converted to succinyl-CoA through three steps: propionyl-CoA carboxylase (biotin-dependent) produces D-methylmalonyl-CoA; methylmalonyl-CoA racemase converts it to L-methylmalonyl-CoA; and **methylmalonyl-CoA mutase** (vitamin B12-dependent) converts it to succinyl-CoA. **Vitamin B12 deficiency** causes methylmalonic acidemia. Succinyl-CoA enters the TCA cycle, representing the only way fatty acid carbons can contribute to gluconeogenesis (via OAA).
### VIII. Ketone Bodies
Ketone bodies are produced in **liver mitochondria** from excess acetyl-CoA when oxaloacetate is diverted to gluconeogenesis during fasting. The three ketone bodies are **acetoacetate**, **beta-hydroxybutyrate** (technically not a ketone), and **acetone** (formed by spontaneous decarboxylation of acetoacetate; exhaled, giving a fruity breath odor).
#### Ketogenesis (Liver)
Ketogenesis begins with thiolase condensing 2 acetyl-CoA to acetoacetyl-CoA. HMG-CoA synthase (the **rate-limiting** enzyme) adds another acetyl-CoA to form HMG-CoA. HMG-CoA lyase cleaves HMG-CoA to acetoacetate and acetyl-CoA. Beta-hydroxybutyrate dehydrogenase reduces acetoacetate to beta-hydroxybutyrate using NADH.
#### Ketone Body Utilization (Extrahepatic Tissues)
The brain (during prolonged fasting), heart, skeletal muscle, and kidney can use ketone bodies. Beta-hydroxybutyrate is oxidized to acetoacetate, which is activated to acetoacetyl-CoA by **thiophorase** (succinyl-CoA:acetoacetate CoA transferase), and then cleaved to 2 acetyl-CoA for the TCA cycle. Thiophorase is **absent in the liver**, ensuring the liver produces but cannot consume ketone bodies.
#### Clinical Significance
**Diabetic ketoacidosis (DKA)** occurs in type 1 diabetes when absent insulin leads to uncontrolled lipolysis, excess acetyl-CoA, and massive ketone body production, causing metabolic acidosis with Kussmaul breathing, fruity breath, dehydration, and hyperglycemia. **Starvation ketosis** is milder; after 2-3 days of fasting, ketone bodies supply approximately one-third of brain energy, rising to up to two-thirds during prolonged starvation, thereby sparing glucose and muscle protein.
A diagram of ketone body metabolism. Panel A: Ketogenesis in the liver showing the pathway from acetyl-CoA to HMG-CoA to acetoacetate (with HMG-CoA synthase as rate-limiting), conversion to beta-hydroxybutyrate and spontaneous decarboxylation to acetone. Panel B: Ketone body utilization in extrahepatic tissues showing beta-hydroxybutyrate conversion to acetoacetate, then to acetoacetyl-CoA (via thiophorase, which is absent in liver), then to 2 acetyl-CoA entering the TCA cycle. Panel C: Metabolic context — during fasting/diabetes, oxaloacetate is depleted (used for gluconeogenesis), so acetyl-CoA from fatty acid oxidation cannot enter the TCA cycle and is diverted to ketogenesis. A clinical inset shows the hallmarks of diabetic ketoacidosis.
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