Atherosclerosis and lipometabolism Flashcards
How do HDLs and LDLs compare in terms of structures?
The components are very similar but the apoprotein is quite different and this is the factor that gives the major properties
How are dietary triglycerides and cholesterol metabolised?
They are broken down and packaged into chylomicrons
Chylomicrons are then broken down into smaller and smaller lipids and into chylomicron remnants- these products can end up in the adipose tissue and blood vessels
Where do most circulating lipids come from?
They are endogenous
Where does a small proportion of lipids end up?
In the walls of blood vessels
What are chylomicron remnants very good at?
Getting into the blood vessel wall- into the tunica intima
They’re very important in the process of atherosclerosis
What is atherosclerosis?
An inflammatory fibre-proliferative disorder
What is the first stage of atherosclerosis development?
LDLs get into the endothelium
What happens once LDLs get into the endothelium?
You get release of growth factors and cytokines which attract inflammatory cells such as monocytes
Formation of foam cells in the endothelium
Proliferation of fibroblasts and smooth muscle cells- expands the plaque
What are foam cells?
Macrophages that contain a lot of lipid
What changes occur that characterise endothelial dysfunction that precede lesion formation?
Greater permeability of endothelium
Up-regulation of leucocytes and endothelial adhesion molecules
Migration of leucocytes into the artery wall
What does the endothelium normally do?
It is an active line of cells that makes growth factors and inflammatory mediators etc
What is the earliest recognisable lesion of atherosclerosis?
The fatty streak
What causes the fatty streak?
Aggregation of lipid-rich foam cells (derived from macrophages and T lymphocytes within the tunica intima)
What do the lesions include later on after the fatty streak?
Smooth muscle cells
In what way are fatty streaks usually formed?
In the direction of blood flow
What causes the formation of a complicated atherosclerotic plaque?
Death and rupture of foam cells in the fatty streak- formation of a necrotic core
What causes formation of the fibrous cap in a complicated atherosclerotic plaque?
Migration of smooth muscle cells into the intimate and laying down collagen fibres results in the formation of a protective fibrous cap over the lipid core
Why is the fibrous cap extremely important?
It separates the highly thrombogenic lipid-rich core from circulating platelets and coagulation factors
What are stable atherosclerotic plaques characterised by?
A necrotic lipid core covered by a thick vascular smooth muscle-rich fibrous plaque
What happens when an atherosclerotic plaque becomes unstable?
The plaque ruptures and exposes the thrombogenic lipid rich core to the circulating platelets and coagulation factors which leads to thrombosis
What else can plaque erosion cause?
Hardening of the arteries which results in weakening and thinning of vessel wall leading to aneurysm and possible haemorrhage
What do complicated atherosclerotic lesions often contain?
Calcium
How can coronary artery disease be detected?
By doing a CT scan of the heart- detects any calcium
What characterises a vulnerable plaque?
Thin fibrous caps
Core rich in lipid and macrophages
Less evidence of smooth muscle proliferation
What is the plaque rupture associated with?
Greater influx and activation of macrophages accompanied by the release of matrix metalloproteinases
What are matrix metalloproteinases involved with?
Breakdown of collagen
What lowers HDL cholesterol?
Smoking and obesity
What type of lipoproteins are easily oxidised?
Small dense LDLs
What type of LDLs cause a lot of atherosclerosis?
Modified LDLs- they can also get through endothelium more easily
What are people with very high triglyceride levels at high risk of?
Pancreatitis
What is the first line treatment for dyslipidaemia?
Statins
What do bile acid sequestrants do?
Lower cholesterol
What is the problem with bile acid sequestrates?
Compliance can be a problem as they cause GI bloating, nausea and constipation
What does nicotinic acid do?
Increase HDL cholesterol
What are the adverse actions of nicotinic acid?
Flushing Skin problems GI distress Liver toxicity Hyperglycaemia Hyperuricaemia
What do fibrates do?
Lower triglycerides
What does probucol do?
Modest effect at lowering LDL cholesterol
What do statins do?
Highly effective at lowering LDL cholesterol
What do statins act on?
The mevalonate pathway to inhibit HMG-CoA reductase
What are two main products of this pathway that are involved in the modification and activation of proteins?
Geranyl pyrophosphate and farnesyl pyrophosphate- small lipids
Can the cell function without geranyl pyrophosphate and farnesyl pyrophosphate or cholesterol?
Can’t function without the lipids but can function without cholesterol
What happens if you block cholesterol synthesis in the liver?
The liver cells respond by making more LDL receptors which then bind to circulating LDL and lower it
Why is the selectivity ratio important?
The higher the selectivity ratio, the greater the likelihood of the molecule being concentrated in the liver cell
What is the important rule of 6 in regards to statins?
If you double the dose of any of the statins, you only get a 6% reduction in LDL cholesterol- this applies to all statins and all doses
What are the side effects of statins?
Pleiotropic- present in some but not others
Also has anti-inflammatory action
What do fibrates do?
Activate PPAR-alpha receptors
What does PPAR stand for?
Peroxisome proliferator activated receptors
What is an example of a PPAR gamma activator and what is it used to treat?
Thiazolidinediones used in type 2 diabetes
What effect do fibrates have?
They lower plasma fatty acids and lower triglycerides- better than statins
Who are fibrates often used in?
Diabetics with high triglycerides
What does ezitimibe do?
Inhibits cholesterol absorption- it is absorbed and then activated as glucuronide
How is ezitimibe commonly given?
As an additional treatment to statins- it decreases LDL further
Which pathway is responsible for breaking down HDL and converting it to LDL?
Reverse cholesterol transport
What protein is responsible for reverse cholesterol transport?
CETP- cholesterol ester transfer protein
What happened when a drug was made that inhibited CETP?
It had a positive effect on increasing HDL and decreasing LDL but it was actually killing people- probably due to increased activation of aldosterone synthesis leading to increased blood pressure
What is PCSK9?
Inhibitor of LDL receptor so stops LDL from reaching the LDL receptor- Monoclonal antibodies have been produced that inactivate this
