10-Mark Answer: Lipoprotein Metabolism, Familial Hypercholesterolemia, and Hyperlipoproteinemia

(A) Metabolism of Lipoproteins with Emphasis on LDL Metabolism (6 Marks)

Overview of Lipoproteins

1. Exogenous (Dietary) Pathway — Chylomicron Metabolism

• Chylomicrons contain apo B-48, apo C-II, and apo E.
• In the capillaries of adipose and muscle, lipoprotein lipase (LPL) — activated by apo C-II — hydrolyses the core triacylglycerol (TAG), releasing free fatty acids for cellular uptake.
• As >90% of TAG is degraded, the particle shrinks into a chylomicron remnant. The C apolipoproteins (but not apo B-48 or apo E) are returned to HDL.
• Chylomicron remnants are taken up by the liver via receptor-mediated endocytosis mediated by apo E, through the LDL (apo B-100/E) receptor and LDL receptor-related protein-1 (LRP-1). Lysosomal hydrolysis releases amino acids, free cholesterol, and fatty acids; the receptor is recycled.

2. Endogenous Pathway — VLDL and IDL Metabolism

• Nascent VLDL contains apo B-100 and acquires apo C-II and apo E from circulating HDL.
• LPL in peripheral tissues hydrolyses VLDL TAG, progressively reducing the particle to IDL (intermediate-density lipoprotein).
• IDL may be:
  • Taken up directly by the liver via the LDL (apo B-100/E) receptor, or
  • Further processed by hepatic lipase → LDL
• Importantly, each LDL particle is derived from a single precursor VLDL particle, as only one molecule of apo B-100 is present and is conserved throughout the cascade. (Harper's Illustrated Biochemistry, 32e, p. 263)

3. LDL Metabolism — Receptor-Mediated Endocytosis ⭐

1. Suppression of HMG-CoA reductase — excess intracellular cholesterol inhibits transcription of the gene for HMG-CoA reductase (via the SREBP-2 pathway), decreasing de novo cholesterol synthesis; the enzyme is also more rapidly degraded.
2. Downregulation of LDL receptors — reduced LDL receptor gene expression via the SRE/SREBP-2 system limits further cholesterol entry, preventing overaccumulation.
3. ACAT activation — excess cholesterol is esterified by acyl-CoA:cholesterol acyltransferase (ACAT) and stored as cholesteryl esters in the cytoplasm.

4. Reverse Cholesterol Transport — HDL Metabolism

(B) Biochemical Defect and Clinical Consequences (2 Marks)

Diagnosis: Familial Hypercholesterolemia (FH)

Molecular Defect

• Mutations in apo B-100 (familial defective apoB) — reduce LDL binding affinity to its receptor
• Gain-of-function mutations in PCSK9 — increase receptor degradation, reducing LDL clearance

Clinical Consequences

(C) Diagnostic and Therapeutic Approaches in Hyperlipoproteinemia (2 Marks)

Diagnosis

• Total cholesterol, LDL-C, HDL-C, triglycerides
• LDL-C >190 mg/dL in adults should prompt FH evaluation

• Family history of premature CVD
• Tendinous xanthomas
• LDL-C levels above age-/sex-specific thresholds
• Genetic testing for LDLR, APOB, PCSK9 mutations confirms diagnosis

• Coronary artery calcium (CAC) score for risk stratification
• Thyroid function (to exclude secondary causes)
• Liver function, renal function (to exclude secondary hyperlipidemia)

Therapeutic Approaches

• Low saturated fat, high fibre diet
• Weight reduction, aerobic exercise
• Smoking cessation

Summary Table

Prostaglandins — 5-Mark Answer

Definition

Precursor Fatty Acid — Arachidonic Acid

• Humans cannot synthesise it de novo
• It is derived from the essential fatty acid linoleic acid (18:2, Δ9,12) — an ω-6 fatty acid obtained from dietary plant oils — through a series of elongation and desaturation reactions in the endoplasmic reticulum
• It is stored esterified at the sn-2 position of membrane phospholipids

Synthesis — The Cyclooxygenase Pathway

• COX activity: converts AA → PGG₂ (with addition of two O₂)
• Peroxidase activity: reduces PGG₂ → PGH₂ (the common intermediate)

• COX-1 — constitutive; present in nearly all tissues including platelets; mediates physiological ("housekeeping") prostaglandin production (gastric protection, platelet function, renal blood flow)
• COX-2 — inducible; expressed at low levels normally but markedly upregulated at sites of inflammation by cytokines (TNF-α, IL-1) and oxidative stress; inhibited by glucocorticoids

Why Are They Called "Local Hormones"?

1. Ubiquitous synthesis — They are produced in minute quantities by virtually all tissues (unlike classical hormones which are made by discrete endocrine glands), wherever stimuli are applied.
2. Local action — They act on or near the cells that produce them (autocrine and paracrine action), not on distant target organs via the bloodstream as classical hormones do. They exert effects at the site of synthesis.
3. Rapid inactivation — They are rapidly metabolised to inactive products at their site of action and do not circulate in the blood in significant concentrations. Half-life in plasma is only seconds to minutes. For example, PGI₂ (prostacyclin) has a half-life of ~2 minutes. This rapid degradation prevents systemic hormonal-like actions.
4. Receptor-mediated mechanism — Like hormones, they act through specific G-protein coupled receptors (GPCRs) on target cell membranes, triggering intracellular second messenger cascades (↑cAMP or ↑IP₃/DAG).
5. Potency at very low concentrations — They exert powerful effects at nanomolar or picomolar concentrations, a hallmark of hormone-like signalling.

"Prostaglandins and related compounds are produced in minute quantities by virtually all tissues. They generally act locally on the tissues in which they are synthesized and are rapidly metabolized to inactive products at their sites of action. Therefore, prostaglandins do not circulate in the blood in significant concentrations." — Lippincott Illustrated Reviews: Pharmacology, p. 1333

Physiological and Pathological Roles of Prostaglandins

• Inflammation: PGs (especially PGE₂) are cardinal mediators of the four signs — they promote vasodilation (redness, warmth), increase vascular permeability (swelling), and sensitise pain receptors (pain). COX-2-derived PGs dominate in inflammation.
• Fever: Bacterial pyrogens → macrophage IL-1 → hypothalamic COX-2 → ↑ PGE₂ → reset thermostat → fever. NSAIDs and aspirin reduce fever by blocking COX.
• Haemostasis: The TXA₂/PGI₂ balance determines platelet aggregation and vascular tone — a critical check in haemostasis.
• Reproduction: PGF₂α stimulates uterine contraction; used clinically to induce labour and terminate pregnancy (e.g., dinoprostone/misoprostol).
• GI protection: PGE₁ and PGE₂ maintain the gastric mucosal barrier. NSAID-induced gastric ulcers result from inhibiting this protective prostaglandin synthesis.
• Renal function: PGs help maintain renal cortical blood flow during states of reduced perfusion; NSAIDs can precipitate acute kidney injury in at-risk patients.

Summary Diagram

Membrane phospholipids
        ↓ (Phospholipase A₂ — activated by stimuli)
  Arachidonic acid (20:4, ω-6)
        ↓ (COX-1 / COX-2)
       PGG₂ → PGH₂
     ↙    ↓    ↓    ↘
  PGE₂  PGD₂  PGF₂α  PGI₂  TXA₂