Lipid Transport Flashcards
How is lipid transported in the blood
Most is transported as lipoprotein particles
2% is carried bound non-covalently to albumin (mostly fatty acids released from lipolysis)
What are lipoproteins made from
Variable amounts of different lipids - phospholipds, cholesterol, TAGs and cholesterol esters
Apoproteins
What are the roles of aplipoproteins
Structural - involved in packaging non-water solube lipids into soluble form as multi-molecular particles
Functional - involved in activation of enzymes or in recognition of cell surface receptors
Describe the structure of a lipoprotein
Spherical shape consiting of a surface coat and hydrophobic core
Surface coat - phospholipids, cholesterol, apoproteins (peripheral and integral)
Hydrophobic core - TAGs and cholesterol esters
Lipoproteins are only stable if they maintain their spherical shape which is dependent on the ratio of core to surface lipids, so as core is reduced, surface coat must be reduced
Name some peripheral apolipoproteins
apoC and apoE
Name some integral apolipoproteins
apoA and apoB
Which are the two importmant apolipoproteins and on which lipoproteins are they found
apoB - VLDL, IDL, LDL
apoAI - HDL
What are the classes of lipoproteins and what do they do
Chylomicrons - transport dietary TAG from intestint to tissues
VLDL - transport TAG from liver to tissue
IDL - short-lived precursor for LDL, transport cholesterol from liver to tissue
LDL - transport cholesterol from liver to tissue
HDL - tranport excess cholesterol from tissue to liver
What enzymes are involved in lipoprotein metabolism
Lipoprotein lipase
Lecithin Cholesterol Acyltransferase (LCAT)
What is lipoprotein lipase
Enzyme found on inner surface of capillaries in muscle and adipose tissue that removes core TAG from lipoprotein particles like chylomicrons and VLDLs
Insulin increases synthesis of the enzyme
It hydrolyses TAG into fatty acids and glycerol, fatty acids taken up by tissues, glycerol taken to liver
Requires ApoC-II as cofactor
What is LCAT
Enzyme that both forms lipoprotein particles and maintains their structure by converting some surface lipid to core lipid
It converts cholesterol to cholesterol ester using fatty acid derived from lecithin
Describe how dietary TAG reaches tissues
TAG hydrolysed in small instestine using pancreatic lipase
Fatty acids enter epithelial cells of small intestine where they are re-esterified back to TAGs
TAGs are packaged with other dietary lipids into chylomicrons with apoB-48 added to the surface
Chylomicrons released into lymphatics
They enter bloodstream as thoracic duct which empties into left subclavian veins where the chylomicron aquires apoC and apoE
Chylomicron is carried to tissue where apoC binds to lipoprotein lipase and TAG is hydrolysed and fatty acids released
Describe how chylomicron ends up at the liver
When TAG reduced to 20% in chylomicron, apoC dissociates and chylomicron forms a chylomicron remnant
Remnant returns to liver where LDL receptor binds apoE and remnant taken up by receptor mediated endocytosis
Describe how a VLDL particle gets from the liver to the tissue
VLDL made in the liver with apoB100 added during formation and apoC and apoE being added later from HDL in the blood
VLDL binds to LPL on capillary endothelial cells and starts to become depleted of TAG
As TAG content of VLDL drops, some VLDLs dissociate from LPL and return to the liver
Describe how a VLDL becomes an LDL
If VLDL depletes to 30%, the particle becomes an IDL particle
IDL can be taken up by liver or rebind to LPL to further deplete TAG content
Upon depletion to 10%, IDL loses apoC and apoE to become an LDL particle (with high cholesterol content)
How do cells obtain cholesterol from LDL particles
Receptor-mediated endocytosis
In this process, LDL particles are taken up by the cell and the cholesterol is released inside the cell
LDL receptors are expressed by cells requiring cholesterol
LDL receptors recognise and bind apoB100, then this complex is taken in by endocytosis and subjected to lysosomal digestion
Cholesterol esters are converted to free cholesterol during this process
This process inhibits synthesis of cholesterol by the cell and reduces synthesis and exposure of LDL receptors
How do LDL particles cause harm to the body
LDL particles have a long half-life so are susceptible to oxidative damage which leads to them being recognised and engulfed by macrophages
Macrophages become foam cells and accumulate in intima of blood vessel wall forming fatty streak
Fatty streak evloves into atherosclerotic plaque which grows and encroaches on lumen - may lead to angina
Plaque may rupture triggering acute thrombosis which may lead to stroke or MI
What inherited condition involves the LDL receptor
Familial hypercholesterolaemia
What is familial hypercholesterolaemia
Where there is an absence or deficiency of functional LDL receptors
So there is elevated levels of LDL and cholesterol in the plasma
What is the function of HDL particles
Transport excess cholesterol from tissues to the liver for disposal and to other cells requiring additional cholesterol
How are HDL particles formed and how do they work
Synthesised by liver and intestine but some bud off from chylomicrons and VLDLs as they are digested
HDL fills with phospholipid and cholesterol and returns to liver to dispose cholesterol as bile salts
ABCA1 protein within cells facilitates transfer of cholesterol to HDL by reverse cholesterol transport
Cholesterol then converted to cholesterol ester by LCAT
How can cells requiring cholesterol obtain it from HDL particles
They utilise a scavenger receptor - SR-B1
What is used to transfer cholesterol ester and TAG between HDL and VLDL particles
Cholesterol exchange transfer protein
What are dyslipoproteinaemias
Any defect in the metabolism of the plasma lipoproteins, either primary or secondary
What are the clinical symptoms of hyperlipoproteinaemias
High cholesterol in blood
Cholesterol deposits in skin:
- Xanthelasma
- Tendon xanthoma
- Corneal arcus
What are the three types of hyperlipoproteinaemias and what causes them
Type I - chylomicrons in fasting plasma, no link with coronary artery disease, caused by defective LPL
Type IIa - associated with coronary artery disease that may be severe, caused by defective LDL receptor
Type III - raised IDL and chylomircon remnants, associated with coronary artery disease, caused by defective apoE
What is the treatment of hyperlipoproteinaemia
Diet and lifestyle modifications
Statins - reduce cholesterol synthesis in liver (inhibits HMG-CoA reductase), also increases expression of lipoprotein lipase
Bile salt sequestrants (cholestyramine) - lowers cholesterol by increasing disposal from the body
