1. Is atherosclerosis a metabolic disease?

2. “Should I get my cholesterol checked?”

3. Macroscopic appearance of atherosclerotic lesions
© Michael Palmer 2014

4. Microscopic appearance of atherosclerotic lesions
© Michael Palmer 2014

5. Development of an atherosclerotic lesion
© Michael Palmer 2014

6. The Scavenger Receptor (SR-A1 receptor)
How macrophages deal with oxidized or modified LDL
The scavenger receptor recognizes modified and/or oxidized LDL and internalizes the modified LDL.
Accumulation of these modified LDL in the cell leads to the accumulation of cholesterol droplets in the macrophage and the formation of foam cells.

7. METABOLIC ASPECTS OF ATHEROSCLEROSIS
cholesterol uptake, synthesis and degradation
cholesterol transport in the circulation: LDL (low density lipoprotein) and HDL (high density lipoprotein)
biochemical changes turn physiological, benign LDL into an atherogenic agent

8. TWO MODES OF UPTAKE OF CHOLESTEROL INTO MACROPHAGES
© Michael Palmer 2014

9. Which modifications of LDL are significant in vivo?
© Michael Palmer 2014

10. How does LDL become oxidized?
Transition metals (Fe, Cu) convert O2 to reactive oxygen species: hydrogen peroxide (H2O2), superoxide (•O–O−)
Lipoxygenases produce lipid hydroperoxy-radicals that can bind to LDL and induce lipid peroxidation

11. Experimental evidence implicating LDL oxidation in the pathogenesis of atherosclerosis
Vitamin E reduces the severity of atherosclerosis in animal models—but not in clinical studies on humans
Antibodies against oxidized LDL are found in blood; among these, IgG promotes atherosclerosis, whereas IgM inhibits it
Haptoglobin alleles differ in the efficiency of hemoglobin clearance, which correlates inversely with susceptibility to atherosclerosis

12. KEY RECEPTORS IN LIPOPROTEIN METABOLISM
• LDL receptor: catabolism of LDL, apoB ligand
• ABCA1 transporter: transports excess cholesterol from cells, apoA-I ligand
• Scavenger receptor A1 (SR-A1): uptake of oxidized and modified LDL by macrophages
• SR-B1 receptor:selective uptake of excess cholesterol from HDL, apoA-I ligand

13. ABCA1 Transporter/Receptor
Large plasma membrane spanning ATP dependent protein.
Essential for moving excess intracellular cholesterol and phospholipid to the plasma membrane.
Acts as a flipase, flipping cholesterol and phospholipid from inner leaflet of plasma membrane to outer leaflet.
Necessary for removing excess cholesterol from foam cells and preventing early steps in atherosclerosis.
ApoA-I is required for capturing the cholesterol released from the foam cell.

14. LIPID'S CAVEOLE AND RAFTS
– structural units of biologic membranes
– membrane microdomains enriched in sphingolipids
and cholesterol – part of plasma membrane signaling
machinery
– they swimm in more fluid phase of membranes
created by glycerophospholipids
FUNCTIONS OF LIPID RAFTS
They play key role in – transcytosis and endocytosis
– signal transmission
– internalisation of toxins, viruses
and bacterias
– cell calcium homeostasis