Flashcards in MEH - Lipid Transport Deck (40):
Name all the different types of lipids
- triacylglycerol (di- and monoacylglycerol)
- fatty acids
- cholesterol (and cholesterol esters)
- vitamins A, D, E and K
What is the normal total cholesterol range in plasma?
Less than 5 mmol/L
What is the difference bwteen phosphatidylcholine and phosphatidylinositol?
They are both phospholipids, but phosphatidylcholine has a choline head while phosphatidylinositol has an inositol head
What is the difference between a liposome and a micelle?
Liposomes are spherical but have a bilayer sheet, while micelles have a single layer of phospholipids with their heads facing outwards and tails inwards in a sphere
Where does the body get cholesterol from?
Some is obtained from the diet, but most is synthesised in the liver
What is cholesterol used for in the body?
- essential component of membranes (modulates fluidity)
- precursor of steroid hormones (cortisol, aldosterone, testosterone, oestrogen)
- precursor of bile acids
How is cholesterol transported around the body?
Esterified with a fatty acid by lethicin cholesterol acyltransferase (LCAT) or acyl CoA: cholesterol acyltransferase, then transported around the body as a cholesterol ester
How are lipoproteins structured?
Phospholipid monolayer with a small amount of cholesterol integrated. They also have integral and peripheral apolipoproteins in their membranes (eg. apoC, apoE, apoA, apoB)
What is the cargo carried by lipoproteins?
- cholesterol esters (cholesterol linked to fatty acids)
- fat soluble vitamins
What are the five classes of lipoproteins?
- VLDL (very low density lipoproteins)
- IDL (intermediate density lipoproteins)
- LDL (low density lipoproteins)
- HDL (high density lipoproteins)
Which classes of lipoproteins are the largest?
Particle diameter is inversely proportional to density, so chylomicrons are the largest and HDL is the smallest.
When are chylomicrons present in the blood?
Normally only 4-6h after a meal
How is lipoprotein density obtained?
What are the six major classes of apolipoproteins?
A, B, C, D, E and H
ApoB and apoAI are important ones
True or false - apolipoproteins are all situated on top of the membrane?
False - they can be integral (passing through the phospholipid bilayer) or peripheral (resting on top)
What are the roles of apolipoproteins?
- packaging water insoluble lipid
- co-factor for enzymes
- ligands for cell-surface receptors
How are chylomicrons metabolised?
- chylomicrons loaded in small intestine and apoB-48 added before entering lymphatic system
- travel to thoracic duct which empties into left subclavian vein, acquire two new apoproteins (apoC and apoE) once in blood
- apoC binds to lipoprotein lipase (found on adipocytes and muscle), releasing its fatty acids to cells
- when triglycerides at around 20%, apoC dissociates and 'chylomicron remnant' remains
- this returns to the liver. LDL receptor on hepatocytes binds apoE and the remnant is taken up by receptor mediated endocytosis
What is lipoprotein lipase?
An enzyme that hydrolyses triacylglycerol in lipoproteins. It requires ApoC-II as a cofactor, and is found attached to the surface of endothelial cells in capillaries
What happens to the remaining contents of chylomicrons once they are returned to the liver?
Lysosomes degrade them into fatty acids, cholesterol and glycerol
Where is VLDL made and why?
VLDL is made in the liver for the purpose of transporting triacylglycerol to other tissues.
How is VLDL metabolised?
Binds to lipoprotein lipase on endothelial cells in muscle and adipose and becomes depleted of triacylglycerol. In muscle, released fatty acids are taken up and used for energy production. In adipose, fatty acids are used for re-synthesis of triacylglycerol and stored as fat
How are IDL molecules formed?
If VLDL content depletes to around 30%, the molecule becomes an IDL particle. These can be taken up by the liver or rebind to the LPL enzyme to further deplete TAG content.
How are LDL particles formed?
When IDL content drops to around 10%, it loses apoC and apoE and becomes an LDL particle
What is the primary function of LDL?
To provide cholesterol from the liver to peripheral tissues
Why are LDLs not cleared efficiently by the liver?
They do not have apoC or apoE so they cannot be cleared efficiently by the liver (liver LDL-receptor has a high affinity for apoE)
What is the clinical relevance of LDL not being cleared effectively by the liver?
The half-life in blood is longer than other types of lipoproteins, meaning that it is more susceptible to oxidative damage. Oxidised LDL is taken up by macrophages that can transform to foam cells and contribute to formation of atherosclerotic plaques
How does LDL enter cells?
- cells requiring cholesterol express LDL receptors on plasma membrane
- apoB-100 on LDL acts as a ligand for the receptors, and the receptor-LDL complex is taken into the cell by endocytosis into endosomes.
- fuse with lysosomes for digestion to release cholesterol and fatty acids
- LDL receptor expression controlled by [cholesterol] in cell
How is HDL formed?
- HDL synthesised by liver and intestine
- can also 'bud off' from chylomicrons and VLDL as they are digested by LPL
- free apoA-I can also acquire cholesterol and phospholipid from other lipoproteins and cell membranes to form nascent-like HDL
How does HDL mature?
- nascent HDL accumulates phospholipids phospholipids and cholesterol from cells lining blood vessels
- hollow core progressively fills and particle becomes more globular
Note - transfer of lipids does not require enzyme activity
What is reverse cholesterol transport?
HDL can remove cholesterol from cholesterol-laden cells and return it to the liver. This is important as it reduces likelihood of foam cell/atherosclerotic plaque formation. ABCA1 protein facilitates transfer of cholesterol to HDL, it is then converted to cholesterol ester by LCAT
What happens to mature HDL?
- taken up by liver via specific receptors.
- cells requiring additional cholesterol can utilise 'scavenger receptor' to obtain it cholesterol from HDL
- HDL can exchange cholesterol ester for TAG with VLDL via action of 'cholesterol exchange transfer protein' (CETP)
What is the transport function of chylomicrons?
Transport dietary triacylglycerol from the intestine to tissues such as adipose tissue
What is the transport function of VLDL?
Transport of triacylglycerol synthesised in liver to adipose tissue for storage
What is the transport function of LDL?
Transport of cholesterol synthesised in liver to tissues
What is the transport function of HDL?
Transport of excess cholesterol from cells to liver for disposal as bile salts and to cells requiring additional cholesterol
What is hyperlipoproteinaemia?
Raised plasma level of one or more lipoprotein classes (there are 6). Caused by defects in lipoprotein lipase, LDL receptors and apoE - others have unknown causes
Give some clinical signs of hypercholesterolaemia
- xanthelasma (yellow patches on eyelids)
- tendon xanthoma (nodules on tendon)
- corneal arcus (obvious white circle around eye)
How does raised serum LDL lead to atherosclerosis?
- Oxidised LDL is recognised and engulfed by macrophages
- lipid laden macrophages ('foam cells') accumulate in intima of blood vessel walls to form a fatty streak
- this evolves into atherosclerotic plaque
- grows and encroaches on lumen of artery, causing angina
- plaque ruptures and triggers acute thrombosis by activating platelets and clotting cascade
- leads to stroke and MI
What is the first line of treatment of hyperlipoproteinaemias?
Changed diet and lifestyle factors:
- reduce cholesterol and saturated lipids in diet, increase fibre intake
- increase exercise
- stop smoking to reduce cardiovascular risk