Lecture 4 Flashcards
What are some types of lipids?
- triacylglycerol (di/monoacylglycerol)
- fatty acids
- cholesterol (cholesterol esters)
- phospholipids
- vitamins ADEK
Why are lipids hard to transport?
They are hydrophobic/lipophilic so it is a problem for them to travel in the blood.
How are lipids transported in blood?
Bound to carriers
- 2% are bound to albumin (has limited capacity)
- 98% carried as lipoprotein particles
What are some typical plasma lipid concentration ranges?
Triacylglycerol: up to 2mmol/L
Cholesterol: <5mmol/L
How is the phospholipid classed?
By the polar head group. (Polar head group linked to phosphate head, it is hydrophilic)
E.g. choline attached to phosphate = phosphatidylcholine
E.g. inositol attached to phosphate = phosphatidylinositol
What is the structure of a phospholipid?
Polar Head: hydrophilic (phosphate and polar head group)
Nonpolar tails: hydrophobic (fatty acid tails)
-2 TAILS (saturated/unsaturated-double bond:kink, allows fluidity)
What structures can phospholipids form?
- bilayer sheet (membrane)
- liposomes (bilayer in a spherical structure-carry things)
- micelles (lipoprotein: single phospholipid layer)
Where do you obtain cholesterol from?
Sometimes from the diet.
Mostly synthesised in liver. (If we don’t get our 1g of cholesterol in a day, we can just synthesise it ourselves)
Why is cholesterol important?
- moderates fluidity of membrane
- precursor of steroid hormones (cortisol, oestrogen, testosterone, aldosterone: all synthesised from cholesterol)
- precursor of bile acids/salts
How is cholesterol transported?
As cholesterol ester.
Addition of fatty acid to a hydroxyl group, eliminating water.
Enzyme:
- LCAT (lecithin cholesterol acyltransferase)
- Acyl-coenzymeA cholesterol acyltransferase
What it a lipoprotein?
Micelles consisting of a single phospholipid sphere, inside is cargo (triacylglyercol/cholesterol ester/vitamins ADEK)
-apolipoproteins attached (apoproteins)
What are some types of apoproteins?
Peripheral: associated with surface of lipoprotein particle. (ApoC/apoE)
Integral: within the phospholipid membrane (apoA/apoB)
What are the 5 classes of lipoproteins?
- chylomicrons (main carrier of triacylglyerol-dietary fat)
- VLDL (very low density lipoproteins- transports fats made in the liver)
- IDL (intermediate density lipoproteins)
- LDL (low density lipoproteins)
- HDL (high density lipoproteins)
What are the main carriers of triacylglycerol?
Chylomicrons
VLDL’s
What are the main carriers of cholesterol esters?
IDL’s
LDL’s
HDL’s
What 3 lipoproteins are related/convert?
VLDL’s convert to IDL’s and then LDL’s over time.
How do you separate lipoproteins?
- flotation ultracentrifugation (HDL are most dense so furthest at the bottom-have the smallest diameter)
- particle diameter is inversely proportional to density (as density increases, diameter decreases)
What are the roles of apolipoproteins?
Structural: package water insoluable lipid
Functional: co-factor for enzymes (can bind enzyme)
-ligands for cell surface receptors
How many classes of apoproteins are there?
6 major classes
A,B,C,D,E,H
What is the role of chylomicrons and how are they metabolised?
Transport dietary fat (triacylglycerol)
- apoB-48 added before entering lymphatic system.
- travel to thoracic duct, empties into left subclavian vein where apoC and apoE are added once in blood
Why is the addition of apoC important on chylomicrons?
It binds lipoprotein lipase (LPL) on capillary walls of adipocytes and muscle
-allows degredation of cargo releasing triacylglycerols inside them (TAG’s can be used as energy in muscle/stored in adipocytes)
- when triacylglycerol content reduced to 20%, apoC dissociates leaving a CHYLOMICRON REMNANT (which returns to the liver)
- chylomicron remnants return to liver
Why is the addition of apoE to chylomicrons important?
Once the chylomicron remnants return to the liver
- LDL receptors on hepatocytes bind to apoE
- chylomicron remnant is taken into hepatocyte via receptor mediated endocytosis
- contents released and metabolised by liver via lysosomes (fatty acids, glycerol, cholesterol)
What is the function of LPL? (Lipoprotein lipase)
To release and degrade triacylglycerides to fatty acids and glycerol from the lipoprotein. (Chylomicron/VLDL)
They can then be used in muscles as energy, or recombined to form TAG stores in adipose tissue.
How is VLDL transported ?
VLDL transports fat made by liver (TAG & cholesterol made in liver) to other tissues.
-apoB100 added to VLDL, as well as apoC & apoE added from HDL’s in the blood
-VLDL binds to LPL on endothelial cells in muscle and adipose tissue and becomes depleted of TAG
(Muscle: fatty acids for energy)
(Adipose: fattty acids for resynthesis or TAG and stored)
Where do VLDL’s go if content is above 30%?
-LPL dissociates from VLDL and complex can return to liver
What are the main function of IDL/LDL particles?
LDL
- provide cholesterol from liver to peripheral tissues
- peripheral cells express LDL receptors and take up LDL via receptor mediated endocytosis, LDL’s can also be reuptaken by liver via same mechanism to release cholesterol/TAG’s
- responsible for formation of atherosclerotic plaques in atherosclerosis
What happens when a VLDL starts to deplete past 30%?
Below 30%:
- Formation of IDL particle (short lived)
- IDL particles can be depleted further by rebinding to LPL/taken back to liver
- if IDL becomes depleted to 10% of original content
- IDL loses apoC & apoE becoming an LDL (high cholesterol content)
What is special about LDL’s?
- Have a very long half life, making them more susceptible to oxidative damage via lipid peroxidation
- oxidised LDL taken up by macrophages forming FOAM cells, contributing to atherosclerotic plaques
- don’t have apoC/apoE so not efficiently cleared by the liver,as hepatocytes have LDL receptor which bind to apoE
Why do LDL enter cells?
Receptor mediated endocytosis.
- cells requiring cholesterol express LDL receptors
- apoB100 on LDL acts as ligand for those receptors
- endocytosis forming and endocytic vesicle
- vesicle fuses with lysosome and contents degraded
- the LDL receptor is degraded or recycled back to cell surface
What is HDL metabolism? (Good cholesterol)
- synthesised by liver OR bud off from chylomicrons/VLDL OR formed from apoA-1
- empty/low levels of TAG
What does apoA-1 do?
-they can acquire cholesterol + phospholipid from other lipoproteins and cell membranes to form HDL’s
What is the function of HDL?
Remove extra cholesterol that cells may have (reverse cholesterol uptake)
- accumulate phospholipids and cholesterol
- particle becomes more globular
- doesn’t require enzymes
What is reverse cholesterol transport?
- HDL’s remove cholesterol
- important for blood vessels as reduces likelihood of foam cells and plaque formation
- ABCA1 protein within cell allows transfer of cholesterol into the HDL particles
- cholesterol converted to cholesterol ester via LCAT
What is considered ‘good/bad’ cholesterol?
LDL carrying cholesterol is bad- leads to atherosclerosis formation
HDL carrying cholesterol is good- removes excess cholesterol from cells and returns it back to the liver
What happens to mature HDL’s?
- taken up by liver via receptors
- cells requiring additional cholesterol e.g. steroidogenic cells to make steroid hormones, utilise SCAVENGER receptor (SR-B1) to obtain cholesterol from HDL’s
- the excess cholesterol once entered into the liver, can be used to make bile
How do HDL’s contain TAG?
They can exchange a cholesterol ester for TAG with VLDL/LDL via cholesterol exchange transfer protein (CETP)
What causes hyperlipoproteinaemias and what are they?
Raised plasma level of one or more lipoprotein classes. Caused by: -over-production -under-removal Defects in: -enzymes -receptors -apoproteins
How many classes of hyperlipoproteinaemias?
6 main classes
What are some clinical signs of hypercholesterolaemia and what is it?
High level of cholesterol in blood- causing deposits of cholesterol to form
- Yellow patches on eyelid (Xanthelasma)
- Nodules on tendon (tendon xanthoma)
- Corneal arcus- white Circe around eye. Common in elderly, not in young so could indicate hyperchoesterolaemia
Formation of atherosclerosis?
Raised serum LDL
- oxidised LDL: lipid inside becomes oxidised (due to longer half life)
- oxidised LDL particle is recognised by macrophages and engulfed
- macrophages become laden with lipid forming FOAM CELLS
- foam cells accumulate in the intima (innermost layer) of the blood vessel walls forming a fatty streak
- fatty streaks can evolve into an atherosclerotic plaque
- plaques can grow and restrict lumen
Symptoms of atherosclerosis?
In coronary artery:
-angina (plaque blocking blood flow, lack of oxygen to myocardium)
Plaque ruptures
-thrombus forms (clot) activating platelets, block entire artery
(In coronary artery= MI, in brain artery = Stroke)
-promotes smooth muscle growth so tunica media gets larger also
How do you treat hyperlipoproteinaemia?
1st approach:
- diet (reduce cholesterol & saturated lipids, increase fibre intake)
- lifestyle (increases exercise & stop smoking- remove oxidative stress)
2nd approach:
- Statins ( reduce synthesis of cholesterol, by inhibiting HMG-CoA) e.g.atorvastatin
- bile salt sequestrants (bind bile salts in GI tract: forces liver to make more bile acids using more cholesterol) e.g.colestipol
How do statins work?
Inhibit HMG-CoA reductase
-catalyses HMG-CoA to mevalonate
Acetyl-CoA > HMG-CoA > mevalonate»_space;>squalene»>cholesterol
Why do you get side effects when using statins?
Because the statin blocks the synthesis of cholesterol strongly and early on so the other metabolites produced in the synthesis are also not produced.
What is the desired non-HDL cholesterol concentration?
4 mmol/L or less
What is the ideal LDL-cholesterol levels?
3 mmol/L or less
What is the ideal HDL cholesterol conc?
Over 1/1.2 mmol/L
Ideal triacylglycerol concentration?
Less than 2 mmol/L
How is apoB-48 derived from apoB-100?
RNA editing.
ApoB-100 is the full size
-RNA from apoB-100 is edited to produce an early stop codon= 48% of original size
How can you distinguish between chylomicrons and VLDL’s?
Chylomicrons contain apoB-48
VLDL’s contain apoB-100
Why do chylomicrons enter the lymphatic system and enter the blood at the left subclavian artery?
To bypass fast metabolism by the liver.
