Biochemistry

Reverse Cholesterol Transport

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LIPOPROTEIN METABOLISM

  • Exogenous pathway: chylomicrons clear dietary lipids
  • Endogenous pathway: VLDL and LDL transport/distribute endogenously synthesized lipids
  • Reverse cholesterol transport: HDL clears excess plasma cholesterol

Enzymes

  • Degrade triacylglycerol to glycerol and free fatty acids
  1. Lipoprotein lipase (LPL), bound to the endothelial layer of peripheral capillaries.
  2. Hepatic lipase, localizes within hepatic endothelial cells.

HIGH DENSITY LIPOPROTEIN (HDL)

  • “Good cholesterol”
  • Transports second most cholesterol (first LDL)
  • Reservoir for lipoproteins

REVERSE CHOLESTEROL TRANSPORT
Step 1: Liver and small intestine synthesize nascent HDL

  • Disc shape with ApoA-I and ApoA-II
  • Heterogeneity exists: nascent HDL may have ApoA-I only, ApoA-II only or both
    Step 2: Nascent HDL picks up free cholesterol from peripheral tissues to become HDL3
    Step 3: Nascent HDL picks up LCAT from plasma as it becomes HDL3

Lecithin acyl transferase (LCAT) esterifies free cholesterol

HDL3

  • Circular HDL particle with CE (esterifies free cholesterol with LCAT)
  • Apolipoproteins on surface: ApoA-I, ApoA-II, ApoE & ApoC-II
  • Circulating lipoproteins donate ApoE and ApoC-II to HDL3
    Step 4: HDL3 picks up more free cholesterol to become HDL2

HDL2

  • Larger HDL particle with more CE (same lipoproteins as HDL3)
  • Contains cholesterol ester transfer protein

Cholesterol ester transfer protein (CETP) transfers lipids between HDL and VLDL

  • Activated by ApoA-II
    Step 5: CETP transfers CE (from HDL) to VLDL, and TAG (from VLDL) to HDL
  • Endogenous pathway: VLDL eventually degrades to LDL (redistributes cholesterol)
    Step 6: HDL2 binds scavenger receptor (SR-B1) on liver
  • HDL2 continues accumulating plasma cholesterol before binding
  • Hepatic lipases degrade TAG & membrane phospholipids: HDL2 –> HDL3
  • Liver converts excess cholesterol to bile salts (digestive elimination)

CLINICAL CORRELATION

Corneal clouding

  • Symptom of LCAT or ApoA-I deficiency
  • HDL cannot esterify cholesterol
  • Leads to rapid HDL degradation: excess cholesterol deposits in cornea and peripheral vessels

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