6 - Lipoproteins Flashcards
What are lipoproteins used for?
Carrying TAG and cholesterol around the body.
Describe the structure of cholesterol.
A largely hydrophobic molecule with a single hydroxyl group at the tip, allowing it to orient itself within lipid bilayers and esterify with fatty acids.
What is cholesterol used for?
Synthesis of steroid hormones and bile acids.
Providing mechanical stability to membranes.
What is the total amount of cholesterol in the body? What proportions are found within the blood and lipoproteins?
140g total
8g in the blood, 5 of which are in lipoproteins.
What is the average daily intake of cholesterol and how much of that is absorbed?
1g, 400mg of which is absorbed.
What is the total turnover through the body of cholesterol?
1g per day.
How much cholesterol is synthesised per day?
600mg
Where is cholesterol synthesised?
The liver.
In what forms and relative quantities does cholesterol enter the latter part of the digestive tract? How much of each is re-absorbed?
1g of simple cholesterol, 18g of bile salts.
All but 0.5g of each is reabsorbed.
How are lipoproteins classed?
By their density.
What is the density of lipoproteins dependent on?
The ratio of TAG to the heavier cholesterol/proteins.
Describe the structure of a lipoprotein.
Large hydrophobic droplet encased in a cholesterol containing lipid monolayer that contains many embedded proteins. One long winding apoprotein wraps around it.
What is the function of apoproteins?
Recognition and binding of lipoproteins to their target cells.
What protein family contains the apoproteins?
Apo
What is the most common apoprotein, and what lipoproteins is it found on?
Apo B-100, which is non-interchangeable on all but chylomicrons.
What difficulties are there in the study of apoproteins?
Because they fold only when they attach to the lipoproteins their structure cannot be analysed by most imaging techniques. They are also thought to undergo large conformational changes depending on the size and content of the lipoprotein.
What methods of study can be used on apoproteins?
Protease susceptibility, ligand receptor analysis and epitope expression.
Where is Apo B-48 found?
The small intestine.
How is Apo B-48 expressed?
It is a truncated apo B-100, translated short due to small intestine expression of an enzyme that modifies a single base pair in the mRNA to produce an early stop codon.
What lipoprotein is Apo B-48 used in?
Chylomicrons.
What is the function of Apo CII?
Allows the lipoproteins to bind to lipoprotein lipase and hence facilitates cargo removal.
How many lipoprotein lipases can bind a single lipoprotein at any given time?
Up to 40.
Which tissue expresses LPLs that do not require CII?
The liver.
What are the five types of lipoprotein?
Chlyomicrons VLDLs LDLs IDLs HDLs
What is the main cargo of chylomicrons?
TAG
What is the main cargo of VLDLs?
TAG
What is the main cargo of IDLs?
TAG and cholesterol.
What is the main cargo of LDL?
Cholesterol
What is the main cargo of HDLs?
Protein
What is the purpose and life cycle of chylomicrons?
To carry TAG produced in the small intestine to the peripheral, releasing FAs all around the body to produce chylomicron remnants that are taken up by the liver.
Where are VLDLs produced, and by what protein?
In the liver by Microsomal Triglyceride Transfer Protein.
What apoproteins can have Apo A reversibly added to them?
Chylomicrons and VLDLs
What apoproteins can have Apo C and E reversibly added to them?
Chylomicrons, VLDLs and HDLs
Which lipoprotein also used Apo E as an integral aproprotein?
IDLs
Which lipoprotein does not use any Apo B proteins, and what integral apoproteins are used instead?
HDLs, AI and AII used instead.
Describe the VLDL cascade.
TAG lipolysis in peripheral tissues turns it into an IDL.
IDLs are harvested by hepatic TAG lipase (HTGL) to make LDLs, which are released and taken up by peripheral tissues that need their cholesterol and cholesteryl esters.
How and why does the fed state affect production and concentration of VLDLs?
Production is decreased to give chylomicrons priority. Extended fed state leads to VLDL buildup as are outcompeted by chylomicrons.
What are LDLs used for?
Transport of cholesterol and cholesteryl esters from the liver to peripheral tissues.
How are LDLs taken up by cells?
By LDL Receptor-mediated endocytosis using a clathrin coated pit which forms an acidic vesicle that merges with the lysosome.
How is the uptake of LDLs controlled by the cell?
LDL receptors are saturated at physiological conditions, so their expression is used to regulate uptake.
How is LDL Receptor regulated?
Expression levels are decreased by the presence of cholesterol.
What are the possible fates of the cholesterol taken up from LDLs?
Transported to the membrane that requires is or, in adipose tissue, added to the lipid droplet after fatty acid esterification by ACAT.
What happens to the cholesteryl esters taken up by cells from LDLs?
Broken down in the lysosome to cholesterol and fatty acids.
How do non-hepatic cells synthesise cholesterol?
HMG CoA Reductase uses Acetyl CoA as a substrate to make cholesterol.
How is HMG CoA Reductase regulated?
Cholesterol inhibits it by decreasing transcription and increasing degradation.
What is the name of the system by which cholesterol affects transcription?
SCAP - SREBP
What does cholesterol bind to to cause a change in transcription?
SCAP (SREBP Cleavage Activating Protein) in the ER
What happens when SCAP is bound by cholesterol?
It binds insig, which causes it to be retained in the ER, and hence not activate the signalling pathway.
What happens when SCAP is not bound to cholesterol?
SCAP binds to SREBP (Sterol regulatory element binding protein), which directs the complex to the Golgi Apparatus. Here the complex recruits an embedded serpin that cleaves SREBP, allowing the SRE domain to dissociate and be cleaved by a metalloprotease thus releasing the signal.
What form does the transcription factor take in SCAP-SREBP signalling?
A Sterol Regulatory Element bound to a transmembrane domain on SREBP. This must be cleaved from SREBP in the golgi before diffusing to the nucleus.
How is SCAP-SREBP signalling turned off?
The SRE transcription factor is quickly degraded within the nucleus, so [cholesterol] must remain low for the pathway to remain active.
What genes does SCAP-SREBP act on?
- LDL Receptor
- HMG CoA Reductase
What is the function of HDLs?
Carrying excess cholesterol/cholesteryl esters to the liver for bile production.
How are HDLs formed?
Secretion of Apo A-I, an amphipathic protein that picks up phospholipids from various membranes until a full HDL is formed.
Why is the rate of HDL formation low?
Most HDLs are recycled instead of absorbed.
What kind of HDL is released from the liver?
Pre-B HDLs
What occurs when the HDLs reach the peripheral tissues?
The Pre-B HDLs are loaded with cholesterol by ABCA1, forming discoidal lipoproteins.
What are discoidal HDLs?
Disc-shaped HDLs which contain large amounts of cholesterol in their membrane, but minimal TAG and cholesteryl esters inside.
What happens to the discoidal HDLs produced in the peripheral tissues?
They are secreted into the lymphatic system and eventually returned to the blood, where LCAT fills them with cholesteryl esters to produce an a-HDL
How does LCAT work?
It produces cholesteryl esters by transfering a fatty acid from a phospholipid to the cholesterol and inserting it into the HDL.
What happens to a-HDLs?
Cholesteryl esters removed by SRB1 in steroidogenic tissues (mostly liver) and any TAG removed by hepatic lipases, producing a pre-B HDL.
Breifly describe the life cycle of a HDL.
Liver makes preB HDL, travels to peripheral tissues in blood. Filled with cholesterol by ABCA1 and secreted into lymph as discoidal HDL. Filled with cholesteryl esters by LCAT in blood. Cholesteryl esters removed by SRB1 in steroidogenic tissues reforming the pre-B HDL.
