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Lipids in Biochemistry - A Complete Guide from Basics

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1. What Are Lipids?

• Compartmentalized (e.g., membrane-associated lipids, TAG droplets in adipocytes), or
• Transported in blood in association with proteins (lipoproteins or albumin)

• Major source of energy (more calorie-dense than carbohydrates or proteins)
• Provide the hydrophobic barrier that partitions aqueous contents of cells
• Fat-soluble vitamins (A, D, E, K) serve regulatory/coenzyme functions
• Prostaglandins and steroid hormones control homeostasis
• Structural components of cell membranes

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2. Classification of Lipids

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3. Fatty Acids - The Building Blocks

3a. Chain Length Classification

3b. Degree of Saturation

• Saturated fatty acids (SFA): No double bonds. The alkyl chain is extended and flexible; carbons rotate freely. Pack tightly together (higher melting point - solid at room temperature). Example: palmitic acid (C16:0), stearic acid (C18:0).
• Monounsaturated FA (MUFA): One double bond. Example: oleic acid (C18:1), found in olive oil.
• Polyunsaturated FA (PUFA): More than one double bond. Double bonds in natural fats are usually 3 carbons apart. Example: linoleic acid (C18:2), arachidonic acid (C20:4).

3c. Cis vs. Trans Configuration

• Cis-unsaturated FA: Have a fixed 30° bend at each double bond because two hydrogens are missing from the same side of the carbon double bond. Cannot pack tightly → lower melting points → liquid oils at room temperature.
• Trans FA: Result from industrial catalytic hydrogenation. Hydrogen is missing from each side of the double bond, so the chain is more linear, resembling saturated FA. Trans fats are solid at room temperature and are associated with increased cardiovascular risk (ASCVD).

In mammals, all naturally occurring unsaturated fatty acids are the cis variety.

3d. Essential Fatty Acids

• Linoleic acid (omega-6) - from plants; converted to arachidonic acid
• Linolenic acid (omega-3) - from plants and marine sources

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4. Triacylglycerols (TAG / Triglycerides)

• The major form of dietary fat (>90% of dietary lipid intake)
• The main energy storage form in adipose tissue
• More energy-dense than carbohydrates: oxidizing 1 mole of palmitic acid (C16) produces ~129 moles of ATP vs. ~38 moles of ATP from glucose

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5. Phospholipids

Glycerophospholipids

• Glycerol backbone with 2 FA chains at positions sn-1 and sn-2
• Phosphate group at sn-3 linked to a polar head group
• Common types:
  • Phosphatidylcholine (lecithin) - most abundant membrane phospholipid
  • Phosphatidylethanolamine (PE) - inner membrane leaflet
  • Phosphatidylserine - inner leaflet, involved in apoptosis signaling
  • Phosphatidylinositol - precursor to second messengers (IP3, DAG)

Sphingomyelin

• Sphingosine backbone (not glycerol)
• One FA attached via amide bond (ceramide)
• Phosphocholine head group
• Major component of myelin sheath

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6. Cholesterol - Structure and Roles

• Four fused hydrocarbon rings (A-D) = the steroid nucleus
• 8-carbon branched hydrocarbon chain at C-17
• Hydroxyl group at C-3 of ring A
• Double bond between C-5 and C-6 of ring B

• Structural component of cell membranes (modulates fluidity)
• Precursor for bile acids
• Precursor for steroid hormones (cortisol, aldosterone, testosterone, estrogen, progesterone)
• Precursor for vitamin D
• ~70% of plasma cholesterol is in LDL

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7. Lipid Digestion and Absorption

• Fatty acids and monoglycerides enter intestinal epithelial cells
• Re-esterified back into TAG in the smooth ER
• Packaged into chylomicrons with apolipoprotein B-48
• Released into lymphatics (not portal blood) via the thoracic duct into the bloodstream

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8. Lipoproteins - Transport in Blood

Types of Lipoproteins

Metabolism Pathways

1. Dietary fat absorbed → chylomicrons assembled in intestinal cells with Apo B-48
2. Enter lymphatics → bloodstream
3. In capillaries: Apo C-II activates lipoprotein lipase (LPL), which hydrolyzes TAG
4. FA taken up by muscle (energy) and adipose (storage)
5. Chylomicron remnants taken up by liver (via Apo E receptor)

1. Liver synthesizes VLDL containing Apo B-100 + TAG
2. VLDL → IDL (after LPL removes TAG) → LDL (after further TAG removal by hepatic lipase)
3. LDL delivers cholesterol to peripheral tissues via LDL receptor (Apo B-100/E receptor)
4. Receptor-mediated endocytosis: LDL binds → clathrin-coated pit → endosome → lysosome → cholesterol released

1. HDL is nascent (disk-shaped) from liver/intestine
2. Acquires cholesterol from peripheral tissues via LCAT (lecithin:cholesterol acyltransferase; activated by Apo A-I)
3. LCAT esterifies cholesterol → moves to HDL core
4. Mature spherical HDL returns to liver → cholesterol excreted in bile

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9. Fatty Acid Synthesis (De Novo Lipogenesis)

Key Steps:

1. Acetyl-CoA exits mitochondria as citrate (CoA cannot cross the inner mitochondrial membrane; acetyl group is shuttled out via the citrate shuttle)
2. Acetyl-CoA carboxylation → Malonyl-CoA (rate-limiting step)
   • Enzyme: Acetyl-CoA carboxylase (ACC)
   • Cofactor: Biotin (Vitamin B7)
   • Requires ATP
   • Activated by: citrate, insulin
   • Inhibited by: palmitoyl-CoA, glucagon, epinephrine
3. Fatty acid synthase (FAS) complex - a multifunctional enzyme that repeats a 4-step cycle:
   • Condensation
   • Reduction (NADPH)
   • Dehydration
   • Reduction (NADPH again)
   • Each cycle adds 2 carbons from malonyl-CoA
   • Product of 7 cycles: Palmitate (C16:0)

Net equation: Acetyl-CoA + 7 Malonyl-CoA + 14 NADPH + 14 H⁺ → Palmitate + 7 CO₂ + 8 CoA + 14 NADP⁺ + 6 H₂O

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10. Fatty Acid Catabolism (Beta-Oxidation)

The Beta-Oxidation Cycle (4 steps per turn):

1. Oxidation (FAD → FADH₂)
2. Hydration
3. Oxidation (NAD⁺ → NADH)
4. Thiolysis - releases acetyl-CoA + shorter acyl-CoA (by 2 carbons)

• 7 turns of beta-oxidation → 8 acetyl-CoA + 7 FADH₂ + 7 NADH
• 8 acetyl-CoA enter the TCA (Krebs) cycle
• Total ATP yield: ~129 moles of ATP per mole of palmitate

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11. Cholesterol Synthesis (Mevalonate Pathway)

Steps:

1. 2 Acetyl-CoA → Acetoacetyl-CoA (thiolase)
2. Acetoacetyl-CoA + Acetyl-CoA → HMG-CoA (HMG-CoA synthase)
3. HMG-CoA → Mevalonate ← RATE-LIMITING STEP
   • Enzyme: HMG-CoA reductase (target of statins)
   • Requires 2 NADPH
   • Inhibited by: high intracellular cholesterol (feedback), statins, bile acids
4. Mevalonate → Isopentenyl pyrophosphate (IPP) (5-carbon isoprene unit)
5. IPP → Geranyl-PP → Farnesyl-PP → Squalene → Lanosterol → Cholesterol
   • Farnesyl-PP is also used for protein prenylation (e.g., Ras protein anchoring)

• Transcriptional: SREBP-2 (sterol regulatory element binding protein) - when cholesterol is low, SREBP-2 is activated → increases HMG-CoA reductase expression
• Post-translational: phosphorylation inactivates; dephosphorylation activates
• Degradation: accelerated by high intracellular cholesterol

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12. Bile Acid Synthesis

• Primary bile acids: Cholic acid (triol) and Chenodeoxycholic acid (diol)
• Rate-limiting enzyme: Cholesterol 7-alpha-hydroxylase (in SER)
• Bile acids are conjugated with glycine or taurine before secretion
• In the intestine, bacteria convert them to secondary bile acids (deoxycholic acid, lithocholic acid)
• ~95% are reabsorbed in the terminal ileum → enterohepatic circulation

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13. Clinical Correlations

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14. Summary Diagram - The Big Picture

Diet (TAG, Cholesterol)
        ↓
   [Gut - Digestion + Emulsification by bile acids]
        ↓
  Chylomicrons (Apo B-48)
        ↓ [LPL in capillaries]
  Fatty acids → Muscle (energy) / Adipose (storage)
  Remnants → Liver

Liver synthesizes:
  Acetyl-CoA → Fatty acids (FAS) → TAG
  Acetyl-CoA → Cholesterol (HMG-CoA reductase ← target of STATINS)
        ↓
  VLDL (Apo B-100) → IDL → LDL
                              ↓
                   Peripheral cells (via LDL receptor)
                              ↓
                   Cholesterol homeostasis (ACAT, SREBP-2)

Peripheral cholesterol → HDL (Apo A-I) → Liver [Reverse cholesterol transport]

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