Lipoprotein Metabolism & Hypolipidaemic Drugs

Part 1 - Lipoprotein Transport Pathways

A. Exogenous Pathway - Chylomicrons (Dietary Fat)

1. Dietary triglycerides (TGs) and cholesterol are absorbed in the intestine, packaged into chylomicrons, and enter the blood via the thoracic duct (lymph system).
2. In capillaries, endothelium-bound lipoprotein lipase (LPL) hydrolyses the TGs into free fatty acids - these pass into muscle (as energy) and fat cells (re-stored as TGs).
3. The remaining particle shrinks into a chylomicron remnant (Chy. rem.) - it is rich in cholesterol ester (CHE) and low in TG.
4. Liver cells have apoprotein receptors that recognize the remnant's surface apoproteins (especially Apo E), so the remnant is engulfed and digested by the liver.
5. Liberated free cholesterol is either stored in liver cells after re-esterification, incorporated into a different lipoprotein, or excreted in bile as cholesterol or bile acids.

B. Endogenous Pathway - VLDL → IDL → LDL

1. Liver secretes VLDL - mainly containing TG and some CHE, along with Apo B-100.
2. In blood, Apo C-II and Apo E are transferred to VLDL from HDL, making it functional.
3. LPL acts on VLDL at capillary endothelium (same as chylomicrons). TGs are hydrolysed - fatty acids go to adipose tissue and muscle. Apo C-II and E are returned to HDL.
4. IDL (Intermediate Density Lipoprotein) is formed - it now contains more CHE than TG.
   • About half of IDL is taken back up by liver via LDL receptors (using Apo E as the ligand).
   • The remaining IDL loses its TGs further and becomes LDL.
5. LDL (low-density lipoprotein) contains only CHE - essentially all TG has been removed.
   • LDL circulates in plasma for a long time.
   • Its uptake into liver and other tissues depends on the cell's need for cholesterol.
   • The rate of LDL uptake is regulated by the rate of LDL receptor synthesis in that tissue.

C. Reverse Cholesterol Transport - HDL

• When cell membranes are degraded, the released cholesterol is rapidly incorporated into HDL.
• HDL esterifies this cholesterol using the enzyme LCAT (lecithin:cholesterol acyltransferase).
• The cholesteryl esters are then transferred back to VLDL or IDL via CETP (cholesteryl ester transfer protein), completing the cycle.
• This reverse transport from tissues back to the liver is why HDL is protective against atherosclerosis.

D. Cholesterol Synthesis in the Body

HMG-CoA → mevalonate (catalysed by HMG-CoA reductase - the rate-limiting step)

E. Fate of Excess Lipoproteins

• Excess lipoproteins in plasma are phagocytosed by macrophages for disposal.
• When too many lipoproteins are phagocytosed, cholesterol is deposited in:
  • Arterial walls → atheromas (plaques causing coronary artery disease)
  • Skin/tendons → xanthomas

Part 2 - Hyperlipoproteinaemias (Raised Blood Lipid Levels)

Causes:

• Diabetes mellitus
• Myxoedema (hypothyroidism)
• Chronic alcoholism
• Nephrotic syndrome
• Drugs: corticosteroids, oral contraceptives, beta-blockers

Part 3 - Hypolipidaemic Drugs: Statins (HMG-CoA Reductase Inhibitors)

Mechanism of Action:

1. Statins competitively inhibit HMG-CoA reductase, the enzyme that converts HMG-CoA to mevalonate (the rate-limiting step of cholesterol synthesis).
2. Reduced intracellular cholesterol synthesis triggers a compensatory increase in LDL receptor expression on liver cells.
3. More LDL receptors means more LDL is cleared from the blood via receptor-mediated uptake.
4. Over the long term, statins reduce both LDL cholesterol and IDL levels substantially.
5. By inhibiting HMG-CoA reductase, they also reduce the body's own cholesterol production pathway.

Key Terms Summary