Fat and Lipids: Chemistry and Metabolism

1. Classification and Structure of Lipids

Fatty Acid Nomenclature

• Saturated FA: No double bonds (e.g., palmitate 16:0, stearate 18:0)
• Monounsaturated FA: One double bond (e.g., oleic acid 18:1Δ9)
• Polyunsaturated FA (PUFA): Multiple double bonds. Two essential PUFAs (cannot be synthesized de novo in humans):
  • Linoleic acid (18:2, ω-6) - precursor of arachidonic acid (20:4, ω-6), a precursor of prostaglandins/leukotrienes
  • α-Linolenic acid (18:3, ω-3)

ω (omega) notation: The ω-6 designation means the first double bond from the methyl (ω) end is at carbon 6. Arachidonic acid (20:4[5,8,11,14]) is an ω-6 fatty acid because the first double bond from the ω end is 6 carbons in. - Lippincott Biochemistry, 8e

2. Lipid Digestion and Absorption

Key Steps

1. Stomach: Lingual and gastric lipases (pH optimum 4-6) hydrolyze short/medium-chain FA from TAG. These enzymes are important in infants and in pancreatic insufficiency (e.g., cystic fibrosis).
2. Emulsification in the small intestine: Bile salts from the gallbladder act as detergents, breaking large fat globules into small micelles, vastly increasing the surface area for pancreatic enzymes. Cholecystokinin (CCK) triggers gallbladder contraction and release of pancreatic enzymes.
3. Enzymatic digestion:
   • Pancreatic lipase (assisted by colipase) cleaves TAG at positions sn-1 and sn-3, yielding 2-monoacylglycerol + 2 free fatty acids
   • Cholesterol esterase hydrolyzes cholesteryl esters to free cholesterol
   • Phospholipases cleave phospholipids to lysophospholipids + FA
4. Absorption into enterocytes: Products are taken up as mixed micelles. Inside the enterocyte:
   • TAG is resynthesized from 2-monoacylglycerol and FA
   • Short/medium-chain FA (≤12C) pass directly into the portal blood
   • Long-chain FA are repackaged into chylomicrons
5. Chylomicron secretion: Chylomicrons enter intestinal lymphatics (lacteals) and drain via the thoracic duct into the subclavian vein.

3. Lipoprotein Transport

Lipoprotein Classes (decreasing size / increasing density)

Chylomicron Metabolism

• After a fatty meal, chylomicrons rise to 1-2% of total plasma and plasma turns turbid/yellow.
• Chylomicron half-life is <1 hour - plasma clears within a few hours.
• Lipoprotein lipase (LPL) on capillary endothelium of adipose tissue, skeletal muscle, and heart hydrolyzes TAG in chylomicrons, releasing FA and glycerol. ApoC-II is the obligatory activator of LPL.
• FA enter adipocytes (storage) or muscle (oxidation); glycerol goes to the liver.
• Chylomicron remnants (depleted of TAG, enriched in cholesteryl esters) are taken up by hepatic ApoE receptors. - Guyton & Hall, Lippincott Biochemistry

VLDL to LDL Pathway

4. Fatty Acid Oxidation (β-Oxidation)

Activation and Transport into Mitochondria

• FA are first activated to acyl-CoA by acyl-CoA synthetase (thiokinase) at the outer mitochondrial membrane, consuming 2 ATP equivalents (ATP → AMP + PPi).
• Long-chain acyl-CoA cannot cross the inner mitochondrial membrane directly. They are transferred to carnitine by carnitine acyltransferase I (CAT I) on the outer membrane - this is the rate-limiting step of FA oxidation.
• The acylcarnitine is transported across the membrane via a translocase, and the acyl group is transferred back to CoA inside the matrix by CAT II.
• Short- and medium-chain FA can enter mitochondria without carnitine.

Carnitine is β-hydroxy-γ-trimethylammonium butyrate, synthesized in the body from lysine and methionine. - Ganong's Review of Medical Physiology, 26e

The Four-Step β-Oxidation Spiral

1. Oxidation (FAD-dependent): Acyl-CoA → trans-Δ2-Enoyl-CoA (produces FADH₂)
2. Hydration: trans-Δ2-Enoyl-CoA → L-3-Hydroxyacyl-CoA
3. Oxidation (NAD⁺-dependent): L-3-Hydroxyacyl-CoA → 3-Ketoacyl-CoA (produces NADH)
4. Thiolysis: 3-Ketoacyl-CoA + CoA → Acetyl-CoA + Acyl-CoA (shortened by 2C)

Energy Yield Example - Palmitate (16:0)

• 7 cycles of β-oxidation → 8 acetyl-CoA + 7 FADH₂ + 7 NADH
• 8 acetyl-CoA × 10 ATP (via TCA) = 80 ATP
• 7 FADH₂ × 1.5 ATP = 10.5 ATP
• 7 NADH × 2.5 ATP = 17.5 ATP
• Minus 2 ATP for activation = ~106 ATP net

1 mol of a six-carbon FA through the TCA cycle yields 44 mol ATP, compared to 38 mol from 1 mol of glucose (6C). FA are ~2.5× more energy-dense than carbohydrates per gram. - Ganong's Review

Regulation of FA Oxidation

• Malonyl-CoA (the first intermediate in FA synthesis) inhibits CAT I, preventing futile cycling of synthesis and oxidation simultaneously.
• In the fed state: high insulin → high malonyl-CoA → FA synthesis ON, FA oxidation OFF.
• In the fasted state: low insulin → low malonyl-CoA → FA oxidation ON.

5. Ketone Body Synthesis (Ketogenesis)

1. 2 Acetyl-CoA → Acetoacetyl-CoA (thiolase)
2. Acetoacetyl-CoA + Acetyl-CoA → HMG-CoA (HMG-CoA synthase)
3. HMG-CoA → Acetoacetate + Acetyl-CoA (HMG-CoA lyase)
4. Acetoacetate → β-hydroxybutyrate (NADH-dependent) or spontaneously decarboxylates to acetone

Normal blood ketone level is ~1 mg/dL. In diabetic ketoacidosis, ketones accumulate because FA oxidation is massively upregulated due to absolute insulin deficiency. - Ganong's Review

6. De Novo Fatty Acid Synthesis

Step 1 - Acetyl-CoA Transport to Cytosol (Citrate Shuttle)

Step 2 - Carboxylation of Acetyl-CoA to Malonyl-CoA (Rate-Limiting Step)

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

• ACC is activated by citrate (allosteric) and by insulin-stimulated dephosphorylation.
• ACC is inhibited by palmitoyl-CoA (product feedback), glucagon/epinephrine (via cAMP → AMPK phosphorylation), and malonyl-CoA availability drives chain elongation.

Step 3 - The FAS Complex (Fatty Acid Synthase)

• Product: Palmitoyl-CoA (16:0) is released by thioesterase
• Requires: 7 ATP (for malonyl-CoA formation) + 14 NADPH

Regulation of Fatty Acid Synthesis

7. Cholesterol Metabolism

Structure

Functions

• Structural component of all cell membranes (modulates fluidity)
• Precursor for bile acids, steroid hormones (glucocorticoids, mineralocorticoids, sex hormones), and vitamin D

De Novo Biosynthesis (Mevalonate Pathway)

1. 3 Acetyl-CoA → HMG-CoA (in cytosol)
2. HMG-CoA → Mevalonate - catalyzed by HMG-CoA reductase (rate-limiting, ER-bound, target of statins)
3. Mevalonate → Farnesyl pyrophosphate (via isoprene intermediates)
4. 2 × Farnesyl-PP → Squalene → Lanosterol → Cholesterol

Regulation of HMG-CoA Reductase

1. Sterol-dependent transcription (SREBP-2 pathway): When ER cholesterol is low, SCAP escorts SREBP-2 to the Golgi, where it is cleaved. Active SREBP-2 enters the nucleus and upregulates HMG-CoA reductase transcription. When sterols are high, SCAP-SREBP is retained in the ER by INSIG proteins.
2. Sterol-accelerated enzyme degradation: High ER sterols promote binding of reductase to INSIG → ubiquitination → proteasomal degradation.
3. Phosphorylation/dephosphorylation: AMPK phosphorylates and inactivates the reductase. Insulin favors the active dephosphorylated form; glucagon and epinephrine favor the inactive phosphorylated form.
4. Hormonal regulation: Insulin activates, glucagon/epinephrine inhibits.

Because AMPK is activated by AMP, cholesterol synthesis is decreased when ATP availability is low - the same condition that inhibits FA synthesis. - Lippincott Biochemistry, 8e

Cholesterol Intestinal Absorption

Bile Acid Synthesis

• Upregulated by cholesterol (via LXR nuclear receptor)
• Downregulated by bile acids (via FXR nuclear receptor)

8. Integration of Lipid Metabolism

• Lippincott's Illustrated Reviews: Biochemistry, 8th ed. - Chapters 15, 16, 18
• Ganong's Review of Medical Physiology, 26th ed. - Chapter 1 (Fatty Acid Oxidation & Synthesis)
• Guyton and Hall Textbook of Medical Physiology - Chapter 69 (Lipid Metabolism)