Lipid Metabolism

Comprehensive overview of lipid anabolism (synthesis) and catabolism (β-oxidation)

Overview of Lipid Metabolism

Energy Storage (Anabolism)

Stored as triglycerides (triacylglycerols)
Location: Adipose tissue (subcutaneous and visceral)
Involves: Fatty Acid Synthase
Occurs when: Organismal energy is high

Energy Liberation (Catabolism)

Breakdown yields: Glycerol + Fatty acids
Glycerol → Glycolysis / Gluconeogenesis
Fatty acids → β-Oxidation → Acetyl-CoA
Occurs when: Organismal energy is low

Core Concept:

Every carbon in cholesterol and fatty acids is derived from acetyl-CoA. Lipid metabolism is highly energy-intensive, requiring significant ATP investment for synthesis but yielding massive ATP returns during oxidation.

Lipid Anabolism (Fatty Acid Synthesis)

Location: Cytosol (for fatty acid synthesis) and Endoplasmic reticulum (for further modifications)

Starting Material: Acetyl-CoA (from pyruvate dehydrogenase or ketogenic amino acids)

Step 1: Acetyl-CoA Transport to Cytosol

Acetyl-CoA cannot cross the mitochondrial membrane directly:

In mitochondria: Acetyl-CoA + Oxaloacetate → Citrate (via citrate synthase)
Citrate is exported from mitochondria to cytosol
In cytosol: Citrate → Acetyl-CoA + Oxaloacetate (via ATP citrate lyase)

Step 2: Formation of Malonyl-CoA

Acetyl-CoA + HCO₃⁻ + ATP → Malonyl-CoA + ADP + Pi

Enzyme: Acetyl-CoA Carboxylase (rate-limiting enzyme)

Energy Cost: 1 ATP per malonyl-CoA (7 ATP total for palmitate synthesis)

Step 3: Fatty Acid Synthase Complex

Multi-enzyme complex that synthesizes palmitate (16-carbon saturated fatty acid) from acetyl-CoA and malonyl-CoA.

Priming:

Acetyl-CoA → Acetyl-ACP (Acetyl transferase)
Acetyl-ACP → Acetyl-KSase (β-ketoacyl-ACP synthase)
Malonyl-CoA → Malonyl-ACP
Acetyl-KSase + Malonyl-ACP → Acetoacetyl-ACP + CO₂

Reduction Cycle (Acetoacetyl-ACP → Butyryl-ACP):

β-Ketoacyl-ACP reductase: Acetoacetyl-ACP + NADPH → D-β-Hydroxybutyryl-ACP
β-Hydroxyacyl-ACP dehydratase: D-β-Hydroxybutyryl-ACP → Crotonyl-ACP + H₂O
Enoyl-ACP reductase: Crotonyl-ACP + NADPH → Butyryl-ACP

Elongation (6 more cycles):

Each cycle adds 2 carbons from malonyl-CoA and requires 2 NADPH. After 7 cycles total, palmitate (16C) is formed.

Step 4: Hydrolysis and Modification

Palmitate released from ACP via thioesterase
Further elongation and desaturation occurs in the endoplasmic reticulum
Can be modified to contain more carbons or double bonds

Energy Investment for Palmitate (16C) Synthesis:

8 Acetyl-CoA required
7 ATP → 7 Malonyl-CoA
14 NADPH → 7 cycles of reduction (2 NADPH per cycle)
Total: 7 ATP + 14 NADPH (equivalent to ~42 ATP)

Step 5: Triacylglycerol Synthesis

Fatty acids are esterified to glycerol to form triglycerides for storage:

Glycerol (from glycolysis or lipolysis) → Glycerol-3-phosphate (1 ATP or 1 NADH)
Glycerol-3-P + Fatty acyl-CoA → Lysophosphatidic acid
Lysophosphatidic acid + Fatty acyl-CoA → Phosphatidic acid
Phosphatidic acid → Diacylglycerol + Pi
Diacylglycerol + Fatty acyl-CoA → Triacylglycerol

Lipid Catabolism (Lipolysis and β-Oxidation)

Occurs when: Blood glucose is low, during fasting, or exercise

Step 1: Lipolysis (Triglyceride Breakdown)

Location: Cytosol of adipose cells

Hormonal Signaling Cascade:

Hormone (epinephrine, glucagon) binds to receptor on adipose cell
Adenylate cyclase activated → ATP → cAMP
cAMP activates Protein Kinase A (PKA)
PKA phosphorylates TAG lipase to active form
Active lipase cleaves fatty acids from glycerol

Sequential Hydrolysis:

Triacylglycerol lipase: TAG → DAG + Fatty acid
Diacylglycerol lipase: DAG → MAG + Fatty acid
Monoacylglycerol lipase: MAG → Glycerol + Fatty acid

Products: Glycerol (→ glycolysis/gluconeogenesis) and Free fatty acids (→ β-oxidation)

Step 2: Fatty Acid Activation

Location: Cytosol

Fatty Acid + CoA + ATP → Fatty Acyl-CoA + AMP + PPi

Enzyme: Acyl-CoA Synthetase

Energy Cost: 1 ATP → AMP (equivalent to 2 ATP)

Step 3: Transport into Mitochondria

Acyl-CoA cannot cross mitochondrial membranes directly. The carnitine shuttle is required:

Outer membrane: Acyl-CoA + Carnitine → Acylcarnitine + CoA(CPT-1: Carnitine palmitoyltransferase I)
Inner membrane: Acylcarnitine crosses via CACT(Carnitine-acylcarnitine translocase)
Matrix: Acylcarnitine + CoA → Acyl-CoA + Carnitine(CPT-2: Carnitine palmitoyltransferase II)
CoA can diffuse back through VDAC; Carnitine is recycled

Step 4: β-Oxidation

Location: Mitochondrial matrix

Function: Cleaves 2-carbon units (Acetyl-CoA) from fatty acyl-CoA, producing NADH and FADH₂

The Four Reactions (per cycle):

Oxidation: Acyl-CoA dehydrogenase
Acyl-CoA → trans-Δ²-Enoyl-CoA + FADH₂
Hydration: Enoyl-CoA hydratase
trans-Δ²-Enoyl-CoA + H₂O → L-β-Hydroxyacyl-CoA
Oxidation: L-Hydroxyacyl-CoA dehydrogenase
L-β-Hydroxyacyl-CoA + NAD⁺ → β-Ketoacyl-CoA + NADH
Thiolysis: Thiolase
β-Ketoacyl-CoA + CoA → Acetyl-CoA + Acyl-CoA (shortened by 2C)

Energy Yield per Cycle:

1 FADH₂ (~1.5 ATP)
1 NADH (~2.5 ATP)
1 Acetyl-CoA (→ TCA cycle → ~10 ATP)
Total: ~14 ATP per cycle

Palmitate (16C) Complete Oxidation

Number of cycles: 7 cycles (16C → 8 Acetyl-CoA)

Source	FADH₂	NADH	Acetyl-CoA	ATP
β-Oxidation (7 cycles)	7	7	8	-
ETC: 7 FADH₂ × 1.5	-	-	-	10.5
ETC: 7 NADH × 2.5	-	-	-	17.5
TCA: 8 Acetyl-CoA × 10	-	-	-	80
Activation cost	-	-	-	-2
Net Total	-	-	-	106 ATP

Odd-Chain Fatty Acids

Rare in mammals, but when they occur, the final cycle produces propionyl-CoA (3C) instead of acetyl-CoA:

Propionyl-CoA + CO₂ + ATP → D-Methylmalonyl-CoA (Propionyl-CoA carboxylase)
D-Methylmalonyl-CoA → L-Methylmalonyl-CoA (Methylmalonyl-CoA racemase)
L-Methylmalonyl-CoA → Succinyl-CoA (Methylmalonyl-CoA mutase, requires vitamin B₁₂)
Succinyl-CoA enters TCA cycle

Ketogenesis (Ketone Body Formation)

Occurs when: Blood glucose is very low (fasting, starvation, low-carb diet) and β-oxidation is high

Location: Liver mitochondria

Function: Provides alternative fuel for brain and other tissues when glucose is scarce

Why Ketone Bodies Form

Excess Acetyl-CoA from β-oxidation exceeds TCA cycle capacity
Oxaloacetate is diverted to gluconeogenesis (low glucose state)
Acetyl-CoA accumulates and enters ketogenesis pathway

Ketogenesis Pathway

Thiolase: 2 Acetyl-CoA → Acetoacetyl-CoA + CoA
HMG-CoA synthase: Acetoacetyl-CoA + Acetyl-CoA + H₂O → HMG-CoA + CoA
HMG-CoA lyase: HMG-CoA → Acetoacetate + Acetyl-CoA
β-Hydroxybutyrate dehydrogenase:
Acetoacetate + NADH → β-Hydroxybutyrate + NAD⁺ (reversible)
Spontaneous: Acetoacetate → Acetone + CO₂ (non-enzymatic decarboxylation)

Three Ketone Bodies:

Acetoacetate: Primary ketone body, can be used by tissues
β-Hydroxybutyrate: Most abundant in blood, used by brain and muscle
Acetone: Volatile, exhaled (causes "ketone breath"), not metabolized

Ketone Body Utilization

Peripheral tissues (brain, heart, muscle) can oxidize ketone bodies for energy:

β-Hydroxybutyrate → Acetoacetate (via β-hydroxybutyrate dehydrogenase, reversible)
Acetoacetate + Succinyl-CoA → Acetoacetyl-CoA + Succinate
Acetoacetyl-CoA + CoA → 2 Acetyl-CoA (via thiolase)
2 Acetyl-CoA → TCA cycle → ATP

Note: Liver lacks the enzyme to utilize ketone bodies, so they are exported to other tissues.

Clinical Significance

Ketosis: Elevated ketone bodies in blood (normal during fasting)
Ketoacidosis: Dangerous condition when ketone bodies lower blood pH (diabetic ketoacidosis)

Lipid Metabolism Summary

Pathway	Location	Key Enzyme	Energy
Fatty Acid Synthesis	Cytosol	Acetyl-CoA Carboxylase, Fatty Acid Synthase	42 ATP invested (palmitate)
Lipolysis	Cytosol (adipose)	TAG lipase, DAG lipase, MAG lipase	No ATP cost
β-Oxidation	Mitochondrial matrix	Acyl-CoA dehydrogenase, Thiolase	106 ATP produced (palmitate)
Ketogenesis	Liver mitochondria	HMG-CoA synthase, HMG-CoA lyase	Provides fuel during fasting