Atherosclerosis and lipid metabolism Flashcards
What are some untreatable and potentially treatable risk factors for CVD?
Untreatable
- Gender –> men > women
- Age –> >45 men, post-menopause women
- Genetic traits
- Psychosocial
- Low socio-economic
- Stressful situations
- Coronary prone behaviour patterns –> Type A behaviour
Potentially treatable
- Smoking and sedentary behaviours
- Dyslipidaemia –> increased cholesterol, TAG, LDL and VLDL lipoprotein levels, decreased HDL
Oxidability ofLDL
Hypertension
Hyperglycaemia, T2D and metabolic syndrome
Pro-thrombic factors –> elevated ability to not break down clots, thrombus formation. Those at risk of CVD might have elevated levels of Plasminogen activator inhibitor which inhibits the breakdown of blood clots, which is dangerous if suffering from atherosclerosis.
High homocysteine levels (produced by liver –> Can inhibit nitric oxide, responsible for vasodilation. Also related to hyperinsulinaemia. Can increase sodium retention which is linked to hypertension
What risk factors for CVD may diet modulate?
Dyslipidaemia
- Increased cholesterol, TAG, LDL and VLDL
- Decreased HDL
Oxidability of LDL
Pro-thrombic factors (PAI-1)
High homocysteine levels (oxidative stress)
Hypertension (Angiotensin –> activates plasminogen activator inhibitor 1
Central obesity, hyperglycaemia, T2D and metabolic syndrome
Why is cholesterol important in diet?
- Hormone production –> precursor to bile acid
- Cell membrane fluidity
Not necessarily needed through diet, however it can be made in the body. If high level are brought in through diet, then the body won’t make as much.
Why should LDL not be between smooth muscle and endothelium?
It can cause damage to the endothelial layer which allows LDL to migrate into that area. Macrophages will engulf LDL and form foam cells. These cells can only expand to a certain point before they become necrotic (producing death of a usually localised area of living tissue) causing the contents to spill out and form the atherosclerotic plaque
What are different types of dietary fat?
- Saturated fatty acids –> storage, quick energy source
- MCFAs
- MUFAs
- PUFAs
- Long chain polyunsaturated fatty acids
- n-3, n-6, n-9 unsaturated fatty acids
- Cis/ trans fatty acids –> rigid structure –> banned in Denmark where a decrease in CVD has been seen
- Cholesterol
What is the danger of having high levels if visceral obesity?
- Altered FFA metabolism
- Altered adipokine release
- Increased liver fat and altered function
- Increased epicardial fat
- Increased muscle fat –> increase in intracellular lipids
- Altered metabolic profile
- Increase risk of stroke, heart disease, T2D
- ‘Active fat’
- Associated with insulin resistance which can lead to glucose intolerance and type 2 diabetes. Visceral fat secretes a protein called retinol-binding protein 4 (RBP4) which has been shown to increase insulin resistance
- Increase in TNFa and Il6
- FFA enter portal veins to the liver where it can influence the production of blood lipids and lead to NAFLD
What fats are the highest in unsaturated fat and saturated fat?
Saturated
- Coconut oil
- Cocoa butter
- Butter
- Lard
Monounsaturated
- Sunflower oil
- Olive oil
- Canola oil
- Peanut oil
How are lipid absorbed?
Food enter intestine from stomach
- Emulsification of fat droplets by bile salts (Bile salts are synthesised by cholesterol)
- Hydrolysis of triglycerides in emulsified fat droplets into free fatty acid and monoglycerides by using pancreatic lipase
- Free fatty acids and monoglycerides are packed into micelles which are coated in bile acids, has a hydrophobic and hydrophilic part.
- Micelles can interact with transporters or diffuse across enterocyte membrane and be reconstituted into triglycerides.
- Taken up by enterocytes
- Triglycerides combine with enzymes and are packaged up in chylomicrons
- Chylomicrons deliver absorbed TAG to cells
Another version
Dietary TAG are emulsified by bile acids (which are synthesised by cholesterol)
Emulsified TAG are hydrolysed into FFA and monglycerides which with pancreatic lipase get packaged into micelles.
Micelles allow absorption of FFA and monoglycerides into the enterocyte/ mucosal cell, which then reassemble as TAG
Triglycerides combine with enzymes and are packaged up into Chylomicrons
Chylomicrons leave the mucosal cells and are released via the lymphatic system, not deposited directly into blood due to large size
Chylomicrons deposited into blood from licelles and acted on by lipoprotein lipase where TAG are cleaved off and enters cell
The removal of triglycerides results in the formation of chylomicron remnants which then binds liver remnant receptor which then causes it to be repackaged and modified to produce VLDL.
What are micelles
What free fatty acids and monoglycerides are packaged into by pancreatic lipase following hydrolysis of emulsified fat droplet.
Coated in bile acids
Once lipids leave, the bile acid conjugates can be taken back to the liver to be recycled and any unabsorbed material exits via faeces
How are lipids secreted from enterocytes?
- Inside enterocyte MAG and FFA re-synthesised into TAG
- TAG packaged with cholesterol and fat soluble vitamins into chylomicrons
- Chylomicrons are lipoproteins –> transport lipids in circulation
- Chylomicrons released by exocytosis from enterocytes
- Too large to enter capillaries so enter lacteals which are lymphatic capillaries that poke up into the centre of each villus.
- Form chyle –> lymph fluid and emulsified fats
- Lacteals to form larger lymphatic vessel
- Chyle transported to the thoracic ducts where it is then emptied into the bloodstream
- Chylomicrons transports TAG where are used in places such as skeletal muscle, cardiac muscle, adipocytes, hepatocytes
What is the generic structure of low density lipoprotein?
LDL
- Hydrophilic surface of phospholipids and free cholesterol
- Hydrophobic core of triacylglycerols, cholesterol esters and lipid soluble vitamins
- Integral apoprotein e.g. apoB100 –> good way of detecting LDL and VLDL in circulation –> crosses into core
- Peripheral apoprotein (on outside) e.g. apoE –> a protein that reacts with an apoE receptor at the liver so it can be internalised and discharge any excess into the liver –> allow cell interaction
LDL, HDL, IDL and VLDL interact with each other and are dependent on each other for their function
Share peripheral apoproteins to allow cell interaction for discharge or take up of contents
Components (hydrophilic coat)
- Phospholipids
- Protein
- Free cholesterol
Cargo (hydrophobic)
- TAG
- Cholesterol esters –> for H bonds with water
Describe chylomicron structure
Very large
Contain TAG –> most of lipid
Little protein –> ApopC 1, 2 and 3 –> can be added in circulation if needed
What is VLDL?
Very low density lipoprotein
- Made by liver to transport lipids to various tissues in the body
- Majority of lipid is triglyceride
- 8% protein –> ApopB100, C 1, 2, ApoE
What is IDL?
Results from catabolism of VLDL
Leftover part after triglyceride removed
Converted to LDL by liver
Major lipid is cholesterol esters –> when in arterial space, as macrophages engulf to form foam cells, esters taken with it which forms plaque.
Proteins 15% –> ApoB100, ApoC, ApoE
What is LDL
Major lipid is cholesterol
Delivers cholesterol from liver to cells
- Cell membranes
- Hormone production
Protein 21% –> ApoB100
Binds to LDL specific receptor
What is HDL?
Made in liver and intestines
Transports cholesterol to liver from cells
Roams bloodstream picking up cholesterol from dying cells and lipoprotein metabolism
Can rescue excess cholesterol from atherosclerotic plaques
Inhibit oxidation of LDL
Major lipid is phospholipid
Protein 50%
- No ApoB
- ApoA, C and E
What is the Chylomicron life cycle?
- Chylomicrons need 3 additional apoproteins from HDL following release into bloodstream (C2 and C3) in order to interact with lipoprotein lipase
- Apoprotein C-II activates Lipoprotein lipase at cell surface, allowing hydrolysis of chylomicron TAG into fatty acids and glycerol. Fatty acids can then be taken up into adipose or muscle tissue
- Apoprotein C-III activate cholesterol esterase allowing cells to take up cholesterol from the chylomicron cholesterol esters
- Apoprotein E is transferred onto lipid depleted chylomicron remnants which binds to hepatic receptors for receptor mediated uptake of chylomicron remnants. Chylomicron remnants will be secreted in VLDL and can be used to produce LDL.
What is the life cycle of VLDL, IDL and LDL?
- VLDL becomes depleted of lipids –> transfer of apoproteins C-I and C-II onto HDL to form IDL
- IDL takes up cholesteryl esters from HDL to become LDL
- LDL is cleared from circulation by receptor mediated uptake in lever
- LDL and LDL-receptor internalised, LDL hydrolysed in lysosomes (macrophages)
- Receptor recycled to surface
What is the life cycle of HDL?
- HDL secreted from liver as a lipid poor protein (empty)
- LCAT (Lecithin Cholesterol Acyl Transferase) enzyme mediates uptake of cholesterol
- Cholesterol in HDL transferred to LDL for receptor mediated uptake in liver
- Empty protein shell
- Apoprotein not internalised - released when lipid removed
What is LCAT?
Lecithin Cholesterol Acyl Transferase
Cholesterol efflux brought about by esterification of cholesterol under the effect of LCAT
LCAT enzyme catalyses the esterification of cholesterol to form cholesteryl ester
HDL gains entry through scavenger receptor SR-B1
How cholesterol is removed from cell
What is atherosclerosis?
Chronic, degeneration, inflammatory condition affecting medium and large arteries
Slow progressive deposition of lipid and matrix proteins in arterial wall
Eventually causes narrowing of the lumen
Clinical features absent until advanced stage which is usually after several decades
Sudden critical reduction in blood supply to affected tissues –> causing ischaemia or infarction
Unstable lesions rupture = haemorrhage into atherosclerotic plaque
The resultant thrombosis (occluding clot) usual cause of myocardial infarction
Injury to endothelium activates genes for expression of adhesion molecules on luminal surface of cells
Monocytes attach to these molecules and then enter the sub-endothelial space
Activated to form macrophage
How are atherosclerotic plaques formed?
Damage to endothelial cells (smoking, hypertension, pollutants, lipids, bacteria, cytokines) Monocytes adhere to endothelial cells. Expression of adhesion molecules
Entry of LDL into sub-endothelial space
Also monocyte-macrophage recruitment (Activation) –> ROS
Damaged LDL
Uptake by macrophages
Injured macrophages –> cytokine and growth factor release from necrosis
Growth factors interact with smooth muscle which causes proliferation.
Foam cells
Plaque –> smooth muscle migration can form a cap on top of the plaque which gets hardened.
Over time, things like hypertension can wear down the cap
What is the biochemistry of CVD?
Dying macrophages produce cytokines which recruit more macrophages -growth factors which encourage growth of smooth muscle
Cholesterol ester accumulates and leads to death of the macrophage
Cholesterol ester and fat in dead macrophages released into sub-endothelial space
Together with foam cells and larger number of smooth muscle fibres they form a plaque
What are some changes that can occur in atherosclerotic plaques?
Atherosclerotic plaques are susceptible to the following pathologic changes with clinical significance
- Rupture, ulceration or erosion (cap weakening - macrophages?)
- Haemorrhage (rupture of neo-vessels which have invaded the plaque)
- Atheroembolism (piece of clot broken off)
- Aneurysm formation (buldge in blood vessel caused by weakness in wall)
Atherosclerosis is a slowly evolving lesion usually requiring many decades to become significant
