16. Atherosclerosis and lipo metabolism Flashcards
What does the exogenous pathway of lipid metabolism involve?
- Dietary triglycerides and cholesterol are broken down and packaged into chylomicrons
- Chylomicrons broken into smaller lipids => chylomicron remnants
- These products can end up in adipose tissue and blood vessels
What does the endogenous pathway of lipid metabolism involve?
- Most circulating lipids are endogenous (80%)
- Lipid generates different lipoproteins, which are broken down and converted
- Some end up with the LDL receptor
Which part of the blood vessel wall are chylomicrons good at getting into?
Tunica intima
What type of disorder is atherosclerosis?
Inflammatory fibro-proliferative
What is reverse cholesterol transport?
- Process where cholesterol is taken out of the blood vessels and foam cells
- HDL => LDL, by cholesteryl ester transfer protein
How are white blood cells involved in athersclerosis?
- Circulating monocyte enters leaky endothelium
- Converted into macrophage
- Ingest lots of lipid to become foam cells
- Foam cells also derived from T-lymphocytes
Outline the progression of atherosclerosis
- LDL moves into the subendothelium
- Oxidised by macrophages and smooth muscle cells
- Release of growth factors and cytokines, which attract inflammatory cells (monocytes)
- Foam cells form in endothelium
- Proliferation of fibroblasts and smooth muscle cells - plaque expands
Describe what happens in the first stage of atherosclerosis (endothelial dysfunction)
- Greater permeability of endothelium
- Up-regulation of leucocytes, endothelial adhesion molecules
- Migration of leucocytes into artery wall
- These all precede lesion formation
Describe what happens in the second stage of atherosclerosis (fatty streak formation)
- Earliest recognisable lesion
- Caused by aggregation of foam cells
- Later on lesions include smooth muscle cells
- Fatty streaks usually formed in the direction of blood flow
- Early stage, and most don’t develop into serious athersclerosis
Describe what happens in the third stage of atherosclerosis (formation of atherosclerotic plaque)
- Death and rupture of the foam cells in the fatty streak
- Necrotic core forms
- Migration of smooth muscle cells into the intima and laying down collagen fibres
- Protective fibrous cap forms over the lipid core
- Stable plaques are characterised by a necrotic lipid core covered by a thick vascular smooth muscle-rich fibrous plaque
Why is the fibrous cap important in a plaque?
Separates the highly thrombogenic lipid-rich core from the circulating platelets and coagulation factors
What characterises an unstable atherosclerotic plaque and what happens if it ruptures?
- Unstable plaque characterised by thin fibrous cap, rich core, less smooth muscle proliferation
- Thrombogenic lipid rich core exposed to circulating platelets and coagulation factors
- Associated with greater influx and activation of macrophages
- Accompanied by the release of matrix metalloproteinases involved in collagen breakdown
- Surge in BP => thrombosis
- Plaque erosion can also lead to the hardening, weakening and thinning of the arteries
- Aneurysm and haemorrhage possible
How can you detect coronary artery disease using a common element/molecule?
- Complicated lesions often contain calcium
- CT scan of the heart can detect calcium
- More calcium in the plaque => more likely to be symptomatic
Why are remnant lipids significant in atherosclerosis and what do remnants include?
- Quite atherogenic
- Lots of remnant lipoproteins in the blood (as a result of fatty meals) => higher risk of CHD
- Includes VLDL, IDL and chylomicron remnants
Why does a stable plaque still cause symptoms?
- Obstruction of blood flow to the heart
* Leads to pain
How does the modification of LDL (e.g. oxidisation) affect its atherogenicity and which molecule can protect it?
- Makes it more atherogenic
* HDL can protect LDL from oxidation
How does a low level of HDL affect the risk for atherosclerosis and CHD?
Increases the risk
What happens to the levels of HDL when triglycerides are high?
Tends to be low
What environmental factors lower HDL levels?
Smoking, obesity and physical inactivity
Can HDL cholesterol be bad?
Yes
• Protection of LDL
• Become bad when oxidised
What is the first line of treatment for dyslipidaemia?
Statins
• Effective in lowering LDL
• Good tolerability profile
How do bile acid sequestrants work and what are the problems with using them?
• Cause body to use more cholesterol to make bile • Effective cholesterol-lowering drugs • Compliance is an issue: - GI bloating - nausea - constipation
How does probucol and fibrates work?
- Probucol - modest effect in lowering LDL
* Fibrates - effective in lowering triglycerides
How do statins work?
- Inhibit HMG-CoA reductase, in the mevalonate pathway
- 2 main products of the pathway = geranyl pyrophosphate + farnesyl pyrophosphate
- These are small lipids, involved in the modification and activation of proteins
- When cholesterol synthesis is blocked, liver makes more LDL receptors
- LDLR binds to circulating LDL, lowering it
What does a higher ‘selective ratio’ mean in context of lipids?
Greater likelihood of the molecule being concentrated in the liver cell
If the number for the potency of a drug is lower, what does this mean for statins?
It is more powerful as an inhibitor of the enzyme
If you double the dose of any statins, how does this effect LDL cholesterol?
6% reduction
What are ‘pleiotropic’ effects of statins?
Effects that are not directly related to the reduction of cholesterol
• e.g. anti-inflammatory
How do fibrates work and who are they given to?
- Activation of PPAR alpha receptors (nuclear receptors)
- Lowers plasma fatty acids and triglycerides
- Reduces inflammation
- Often used in diabetics with high triglycerides
- Reduces inflammation
- Often used in diabetics with high triglycerides to reduce acute pancreatitis risk
- Given to patients with low HDL and LDL
How does nicotinic acid work?
• Lowers LDL
• Increases HDL
• Lower triglycerides
• Increases fibrinolytic activity
• Not well tolerated, so not used much in clinical practice, despite effectiveness:
- flushing, skin problems, GI distress, liver toxicity, hyperglycaemia, hyperuricaemia
How does ezetimibe work?
- Inhibits cholesterol absorption
- The drug is absorbed and activated as glucuronide
- Reduces LDL cholesterol
- Useful as an addition to statins
What is responsible for the breakdown of HDL into LDL?
Cholesteryl ester transfer protein (CTEP)
How effective were CETP inhibitors?
- Increase HDL and decrease LDL
- They were killing people in expanded clinical trials
- Torcetrapib had off-target adverse effects (i.e. unpredictable)
- Could have been due to the activation of aldosterone synthesis => increased BP
What is PCSK9 and how is it significant in cholesterol lowering treatment
- Inhibitor of the LDLR
- Stops LDL from reaching the LDLR
- Unfortunately statins increase PCSK9 (as well as LDLR)
- Therefore, monoclonal antibodies have been produced to inactivate PCSK9
- This allows the LDL receptor to continue working, lowering the circulating LDL levels
What patients appear to have the greatest need for PCSK9 inhibition therapy?
Familial hypercholesterolaemia patients
