Chapter 17 – Fatty Acid Catabolism Study Notes

Lipid Functions and Storage

• Major physiological roles of lipids
  • Stored in white adipose tissue as triacylglycerols (TAGs)
  • Serve as long-term energy reserves
  • Provide insulation, mechanical protection for vital organs, and thermal regulation (heat generation in brown fat)
  • Precursors/sources for membrane lipids, signaling molecules, and metabolic water (e.g., camel hump)
• Comparative advantages of fats over polysaccharides
  • Carry more energy per carbon because fatty-acyl chains are highly reduced
  • Carry less associated water because non-polar ⇒ higher energy density
  • Glycogen/glucose: short-term, rapid delivery
  • TAGs: long-term (months) storage, slow release
• Energetic statistics
  • ≈ $\tfrac13$ of human daily energy from dietary TAGs
  • ≈ $80\%$ of heart & liver ATP obtained by FA oxidation
  • Hibernators (grizzly bears) & migrating birds rely almost exclusively on fat; camels oxidize fat for both ATP & metabolic $\text{H}_2\text{O}$

Digestion, Absorption & Transport of Dietary Lipids

• Sequence of events (small intestine → tissues)
  1. Bile salts (liver, gallbladder) emulsify dietary fats into mixed micelles
  2. Intestinal lipases hydrolyze TAGs → free FAs + mono-/di-acylglycerols + glycerol
  3. Enterocytes re-esterify products → TAGs
  4. TAGs + cholesterol + apolipoproteins (ApoB-48, ApoC-II, ApoC-III) assemble into chylomicrons
  5. Chylomicrons released to lymph → blood
  6. Lipoprotein lipase (activated by ApoC-II) at capillary endothelium hydrolyzes TAGs → free FAs + glycerol
  7. Free FAs enter myocytes/adipocytes via FA transporters; fate
  • Oxidized for ATP
  • Re-esterified for storage
• Lipoprotein composition (chylomicron)
  • TAG core, cholesteryl esters; surface monolayer of phospholipids + apolipoproteins

Hormonal Mobilization of Stored TAGs

• Low blood glucose ⇒ glucagon (or epinephrine) signaling
  1. Hormone binds GPCR ⇒ $\uparrow$ cAMP ⇒ PKA activation
  2. PKA phosphorylates
  • Perilipin coat proteins → exposes lipid droplet
  • Hormone-sensitive lipase (HSL)
  1. CGI-58 dissociates, activates ATGL (adipose TAG lipase): TAG → DAG + FA
  2. HSL: DAG → MAG + FA; MAGL: MAG → glycerol + FA
  3. FAs leave adipocyte, bind serum albumin (7 FA/albumin) → delivered to energy-demand tissues
  4. Inside myocyte: FA → β-oxidation → $\text{CO}_2$ + ATP for contraction

Glycerol Utilization

• Released glycerol (from lipolysis) enters hepatocyte
  • Glycerol kinase: glycerol + ATP → $\text{Gly3P}$ + ADP
  • Glycerol-3-P dehydrogenase: $\text{Gly3P} + \text{NAD}^+ \rightarrow \text{DHAP} + \text{NADH} + H^+$
  • DHAP ↔ GAP → glycolysis or gluconeogenesis
• Energetics: input 1 ATP, produce 1 NADH (≈2.5 ATP) ⇒ net positive; enables limited anaerobic use of fat-derived carbon

Activation of Fatty Acids to Fatty-Acyl-CoA

• Cytosolic (outer-mitochondrial-membrane) acyl-CoA synthetase (thiokinase)
  • Reaction: $\text{FA} + \text{CoA} + \text{ATP} \rightleftharpoons \text{Acyl-CoA} + \text{AMP} + 2\text{P}_i$
  • $\Delta G^{\circ'} \approx -34\ \text{kJ·mol}^{-1}$ (ATP → AMP PPi cleavage)
• Required for β-oxidation, membrane incorporation, or esterification

Carnitine Shuttle – Mitochondrial Import ((>12) C)

• Step 1 (Cytosolic side): Carnitine acyltransferase I exchanges CoA for carnitine → acyl-carnitine
• Step 2 : Acyl-carnitine/ carnitine antiporter crosses inner membrane
• Step 3 (Matrix): Carnitine acyltransferase II regenerates acyl-CoA + free carnitine (returns to IMS)
• Regulatory point: Malonyl-CoA (from FA synthesis) inhibits CAT I ⇒ prevents futile cycling

Three Stages of Complete FA Oxidation

1. β-Oxidation (mitochondrial matrix): progressive removal of 2-C units as acetyl-CoA + $\text{FADH}_2 + \text{NADH}$
2. TCA cycle: acetyl-CoA → $2\,\text{CO}<em>2 + 3\,\text{NADH} + \text{FADH}</em>2 + \text{GTP}$
3. Oxidative phosphorylation: $\text{NADH},\,\text{FADH}_2$ donate e⁻ to respiratory chain → ATP

β-Oxidation Cycle – Four Reactions

• One cycle output: 1 acetyl-CoA, 1 FADH₂, 1 NADH; chain shortened by 2 C
• Trifunctional Protein (TFP) (α₄β₄) on inner membrane handles C≥12 simultaneously performing steps 2–4 (substrate channeling)

Energetics Example – Palmitate (C16:0)

• 7 β-oxidation cycles → 8 acetyl-CoA + 7 NADH + 7 FADH₂
• ATP yield (P/O ratios $1\,\text{FADH}_2=1.5$, $1\,\text{NADH}=2.5$):
  • β-Oxidation: $7(1.5+2.5)=28\ \text{ATP}$
  • TCA (per acetyl-CoA): $10\ \text{ATP}$ ⇒ $8 \times 10 = 80\ \text{ATP}$
  • Total: 108 ATP per palmitoyl-CoA (net 106 after subtracting 2 ATP equivalent used for activation)
• Overall coupled reaction:
  $\text{Palmitoyl-CoA} + 23\,\text{O}<em>2 + 108\,\text{ADP} + 108\,\text{P}</em>i \rightarrow 108\,\text{ATP} + 16\,\text{CO}<em>2 + 23\,\text{H}</em>2\text{O} + \text{CoA}$

Oxidation of Unsaturated Fatty Acids

• Problem: natural cis-double bonds; enoyl-CoA hydratase requires trans-Δ²
• Enzymatic solutions
  • Δ³,Δ²-Enoyl-CoA isomerase: cis-Δ³ → trans-Δ² (used for odd-numbered double bonds, e.g., oleate)
  • 2,4-Dienoyl-CoA reductase + NADPH: converts trans-Δ², cis-Δ⁴ to trans-Δ³; followed by isomerase (needed when even-numbered cis bonds present, e.g., linoleate)
• Result: enables entry back into standard β-oxidation; costs 1 NADPH per even double bond (slightly less ATP yield)

Oxidation of Odd-Numbered Fatty Acids

• Final three-carbon fragment = propionyl-CoA
• Conversion to TCA intermediate (succinyl-CoA):
  1. Propionyl-CoA carboxylase (biotin, ATP, $\text{HCO}_3^-$) ⇒ D-methylmalonyl-CoA
  2. Methylmalonyl-CoA epimerase ⇒ L-isomer
  3. Methylmalonyl-CoA mutase (coenzyme B₁₂) ⇒ succinyl-CoA
• Net cost: 1 ATP; unique requirement for vitamin B₁₂

ω-Oxidation (ER) & α-Oxidation (Peroxisome)

• ω-Oxidation
  • Initiates at the terminal (ω) carbon, introduces hydroxyl → carboxyl ⇒ dicarboxylic acids → chain-shortened in mitochondria
  • Minor pathway in humans; up-regulated when β-oxidation defective; prefers C10–C12 substrates
• α-Oxidation
  • Removes one C from carboxyl end; required when β-C is blocked (e.g., phytanic acid with β-methyl)
  • Occurs in peroxisomes; deficiency → Refsum disease (phytanic acid accumulation)

β-Oxidation in Peroxisomes/Glyoxysomes (Plants & Some Tissues)

• Handles very-long-chain FAs ((>20) C)
• Acyl-CoA oxidase transfers e⁻ from FADH₂ directly to $\text{O}<em>2$ ⇒ $\text{H}</em>2\text{O}_2$ (cleared by catalase); no ATP captured ⇒ heat
• NADH exported to mitochondria; acetyl-CoA enters glyoxylate cycle in seeds ⇒ gluconeogenesis (sucrose for germination)

Regulation of FA Metabolism

• Key node: Carnitine acyltransferase I
  • Inhibited by malonyl-CoA (product of acetyl-CoA carboxylase, ACC)
  • ACC active (de-P, insulin, high glucose) ⇒ FA synthesis on, β-oxidation off
  • ACC inactive (P by PKA, glucagon/epinephrine, low glucose) ⇒ β-oxidation on
• ATP/ADP, NADH/NAD⁺ ratios feedback-inhibit TCA & β-oxidation

Ketone Bodies – Formation & Utilization

• In liver mitochondria when oxaloacetate depleted (fasting, high FA influx, diabetes)
  • 2 acetyl-CoA → acetoacetyl-CoA (thiolase)
  • +acetyl-CoA + $\text{H}_2\text{O}$ → HMG-CoA (HMG-CoA synthase)
  • Split → acetoacetate + acetyl-CoA (HMG-CoA lyase)
  • Acetoacetate ↔ D-β-hydroxybutyrate (NADH-dependent) or → acetone (spontaneous decarboxylation; exhaled odor)
• Exported to blood; extra-hepatic tissues express β-ketone body CoA transferase (thiophorase)
  • Succinyl-CoA + acetoacetate → acetoacetyl-CoA + succinate
  • Thiolase: acetoacetyl-CoA → 2 acetyl-CoA → TCA.
• Brain adapts to ketones during prolonged starvation; over-production → ketoacidosis (↓pH)

Learning Checklist / Exam Targets

• Carnitine shuttle: steps, regulation (Fig 17-6)
• Glycerol entry into glycolysis (Fig 17-4)
• Full β-oxidation cycle: substrates, enzymes, cofactors, energetics (Fig 17-8a)
• Special pathways: ω-, α-, unsaturated, polyunsaturated, odd-chain FA oxidation
• Ketone body synthesis & utilization; physiological roles (p 686–688)
• Comparative β-oxidation in mitochondria vs peroxisomes