S2 Lipid Transport Flashcards
How are lipids transported in blood? (2 ways)
- mostly carried as lipoprotein particles
* some are carried bound to albumin (has limited capacity)
How is cholesterol obtained and transported?
Obtained from the diet and some is synthesised by the liver
Transported as a cholesterol ester (addition of a fatty acid)
What is cholesterol a precursor for?
- steroid hormones e.g. cortisol, oestrogen, aldosterone and testosterone
- bile acids
What is the structure of lipoproteins?
- phospholipid monolayer with a small amoutn of cholesterol present
- cargo consisting of: TAG, cholesterol ester and fat soluble vitamins
- integral and peripheral apolipoproteins
What are the five classes of lipoprotein?
- Chylomicrons
- VLDL - very low density lipoproteins
- IDL - intermediate density lipoproteins
- LDL - low density lipoproteins
- HDL - high density lipoproteins
What do chylomicrons transport?
Dietary fat
What do VLDL evolve into? And what does that then evolve into?
IDL
LDL
What is the good and bad cholesterol?
Good - HDL
Bad - LDL
Which lipoproteins are the main carriers of fat?
Chylomicrons and VLDL
Which lipoproteins are the main carriers of cholesterol esters?
IDL, LDL and HDL
What are apolipoproteins?
- proteins associated with lipoproteins
- there are 6 major classes - ABCDEH
- apoB (VLDL, IDL and LDL) and apoAI (HDL) are important
- they can be peripheral or integral
What are the two roles of apolipoproteins?
- Structural - package water insoluble lipids
2. Functional - cofactors for enzymes and ligands for cell surface receptors
How does chylomicron metabolism occur?
- Chylomicrons are loaded in the s. intestine with e.g. fat, cholesterol and vitamins and apoB-48 is added
- Transported through in the lymph and empties in blood through left subclavian vein (apoC and apoE are added)
- apoC binds to lipoprotein lipase (LPL) which is on the capillary walls at muscle and adipose tissue
- It releases fatty acids into the cells and the chylomicron remnants return to the liver
- The LDL receptor on hepatocytes binds to apoE and the chylomicron remnants are taken up by receptor mediated endocytosis
- Lysosomes release the remaining contents for use in metabolism
How does VLDL metabolism occur?
- VLDL is made in the liver to transport TAG to other tissues
- apoB100, apoC and apoE added to VLDL
- VLDL binds to LPL on endothelial cells in muscle and adipose tissue and TAG is released into the tissue cells
- In the muscle the fatty acid are used for energy production
- In adipose the fatty acid are used to resynthesise TAG and store it as fat
How does IDL and LDL metabolism occur?
- The TAG content of VLDL occurs, some VLDL dissociates for the LPL enzyme complex and are returned to the liver
- If the VLDL content depletes to about 30%, the particle becomes a IDL particle
- IDL can be taken upon but the liver or remind to LPL to further deplete TAG content
- If the IDL content depletes to about 10%, IDL loses apoC and apoE and comes an LDL particle
What is the function of LDL?
Provide cholesterol from the liver to peripheral tissues which have LDL receptors so take up LDL via receptor mediated endocytosis
What apolipoproteins don’t LDL have? What does this mean?
apoC and apoE
Not efficiently cleared by the liver as liver LDL receptor has a high affinity for apoE
Which has the longest half life, VLDL, IDL or LDL? What does this mean clinically?
LDL
It is more susceptible to oxidation damage
If LDL is oxidised, macrophages take it up and transform into foam cells which contribute to atherosclerosis
Describe receptor mediated endocytosis. And what happens if the molecule/particle is to be digested?
A ligand binds to receptors on the cell surface leading to endocytosis into endosomes (vesicles).
The endosome fuses with a lysosome
What controls LDL receptor expression?
The cholesterol concentration in a cell
What happens in the synthesis of HDL?
- New HDL is synthesised by the liver and intestine or can “bud off” from chylomicrons and VLDL (as digested by LPL)
- apoA-I can get cholesterol and phospolipid from other lipoproteins and cell membranes to form ‘new-like’ HDL
What happens in the maturation of HDL?
- New HDL accumulates phospholipids and cholesterol from cells lining blood vessels
- The hollow core fills and the particle (HDL) becomes more globular
Does transfer of lipids to HDL require enzyme activity?
No
What does HDL do? Why is this good?
Reverse cholesterol transport
HDL can remove cholesterol from cells containing LOTS of cholesterol and return it to the liver
It reduces the likelihood of foam cell and atherosclerosis formation
What protein facilitates transfer of cholesterol to HDL?
What then converts cholesterol to cholesterol ester?
ABCA1 protein
LCAT
What is the fate of mature HDL?
- Taken up by the liver via receptors
- Cells that need extra cholesterol can utilise a scavenger receptor to get cholesterol from HDL
- HDL can exchange cholesterol ester for TAG with VLDL via cholesterol exchange transfer protein (CETP)
What cells may need extra cholesterol?
Cells involved in steroid hormone synthesis
How is cholesterol disposed of in the liver?
Converted into bile salts (or is transported to cells requiring additional cholesterol)
What is the general role of VLDL, IDL and LDL?
VLDL - transports TAG synthesised in the liver to adipose tissue for storage
IDL - transports cholesterol synthesised in the liver to tissues (a short-lived precursor)
LDL - transport of cholesterol synthesised in the liver to tissues
What are hyperlipoproteinaemias? What causes it?
Raised plasma level of lipoprotein(s)
Caused by over-production or under-removal due too defects in enzymes, receptors and apolipoproteins
What are the clinical signs of hypercholesterolaemia?
- high levels of cholesterol in the blood
- cholesterol deposits in areas of the body
E.g. xanthelasma- yellow patches on eyelids
tendon xanthoma- nodules on tendon
corneal arcus - white circle around eye (common in old people, but not young people)
How does oxidised LDL lead to atherosclerosis?
- Oxidised LDL
- Macrophages recognise and engulf
- Macrophages containing lipid called foam cells. These accumulate in the tunica intima of blood vessel walls and form a fatty streak
- The fatty streak can evolve into atherosclerotic plaque
- This plaque can grow and block the lumen of the artery (e.g. coronary artery) and can cause angina or can rupture triggering thrombosis which block the arteries (e.g. coronary artery or brain) leading to myocardial infarction or a stroke
How can hyperlipoproteinaemias be treated?
- reduce cholesterol and saturated lipids in diet and increase fibre intake
- increase exercise
- stop smoking
- use statins to reduce cholesterol synthesis
- use bile salt sequestrants
How do statins reduce cholesterol synthesis?
By inhibiting HMG-CoA reductase
What do bile salt sequestrants do?
Bind bile salts in the GI tract which forces the liver to produce more bile acids, using more cholesterol in the process
How does an increase in fibre intake treat hyperlipoproteinaemias?
Allows excretion of bile salts, instead of the bile salts being reabsorped and reused, so liver needs to use more cholesterol to produce more bile salts
