Lipoprotein Handling Flashcards
Where do most fatty acids come from?
- Most Fatty acids come from the diet in the form of triglycerides (90%), cholesterol, cholesterol esters, phospholipids or free fatty acids (FA)
o FA can be synthesized in the liver during excess energy intake.
What is the issue with triglycerides and cholestrols?
- Issue with triglycerides & cholesterols – highly hydrophobic
o Cannot be transported in the blood as they are, so have to be packed in a lipid/protein coat forming lipoproteins
What comprises the outer coat of lipoproteins?
- Outer coat:
o Phospholipids (amphiphatic)
o Free cholesterol (also amphiphatic)
o Proteins – called apoproteins
What comprises the inner core of lipoproteins?
- Inner core (transport material): o Cholesterol o Cholesterol esters o Triglycerides o Some vitamins (such as A and E)
What do lipoproteins transport fats and cholesterols between?
o The gut (digested food) and the rest of the body
o The liver and peripheral tissues
o Peripheral tissues back to the liver
What are the major differences between different lipoproteins?
o Size
o Fat and cholesterol content
o Different apoproteins, which determine:
o The fate of the lipoprotein (where it goes)
o The interactions of the lipoprotein
o Can also inhibit/activate certain enzymes
Where do the different lipoproteins carry fats and cholesterols to and from?
- Chylomicrons – formed in the gut during digestion - carry fat/cholesterol from GI to peripheral tissues
- VLDL – formed in the liver (from excess energy and leftovers from chylomicrons) - distribute triglycerides to peripheral tissues
- IDL – formed from VLDLs that have had triglycerides absorbed from peripheral tissue
- LDL – represent remnants of the VLDL and IDL which go back into circulation to deliver cholesterol to peripheral cells
- HDL – scavengers of cholesterol from peripheral cells and returns excess cholesterol as cholesterol esters to the liver to be used to form VLDLs and LDLs.
What are chylomicrons formed from? Where are they absorbed? Where do they travel to and what do they interact with along the way?
- Chylomicrons are formed from fats and cholesterol absorbed from the GI and pass into the lymphatic system prior to the blood. In lymphatic system, chylomicrons interact which HDL which donate Apo E and C2 (important to determine the fate of the chylomicrons).
o ApoC2 – allows the chylomicron to give its triglycerides to peripheral cells
o ApoE - allows the chylomicron remnant to be taken up by the liver to deliver fatty acids and cholesterol.
How are VLDL formed? How is this different to chylomicrons?
- Very similar to chylomicron formation except vldl are produced by the liver
- Also require addition of ApoC2 and ApoE from HDLs to form mature VLDLs.
- Remnant VLDLs are either re-absorbed by the liver or go on to become LDLs.
What is lipoprotein lipase? Why is Apo C2 important for it? What happens to LPL activity during starvation and after meals?
- Main regulator of triglyceride transfer from VLDL and chylomicrons to target cells – referred to as the gatekeeper of lipoprotein metabolism
- Lipoprotein lipase (LPL) is the enzyme responsible for breaking down triglycerides in chylomicrons and VLDLs into free fatty acids which can be taken up by peripheral cells.
- Apo C2 (on chylomicrons and VLDLs) is important for the activation of LPL on the luminal surface of capillaries.
- During starvation:
o LPL activity is highest in muscle where FA are used for energy in the TCA cycle - After a meal:
o LPL activity is highest in adipose cells to form fat by the process of esterification - So chylomicrons and VLDLs transfer mainly triglycerides not cholesterol (that is done by LDLs)
What is the function of low-density lipoproteins? Which enzymes are involved and which protein is involved?
- Function of LDL is to deliver cholesterol to peripheral cells of the body
- LDLs are formed by what remains of the VLDLs after they have distributed most or all of their triglycerides to extrahepatic cells of the body.
- As VLDLs lose triglycerides, they become more dense and form IDLs. IDLs are absorbed by the liver where the enzyme hepatic TAG ligase (HTGL) converts IDL to cholesterol rich LDL having only one apoprotein Apo B100.
- ApoB100 is an important protein because it binds to LDL receptors on the surface of target cells and allows receptor-mediated endocytosis to occur – process by which cholesterol is taken up by target cells (different from chylomicrons/VLDL)
What is cholesterol? How is it synthesised? What do high cholesterol levels do, and how is cholesterol production reduced?
- Cholesterol is a fundamental molecule used in cell membranes, used in biosynthesis of steroid hormones and in the formation of bile acids.
- Most cells can also synthesize cholesterol from acetyl coA using a key enzyme HMG-coA reductase.
- High cholesterol levels induce negative feedback on cholesterol production and intake by:
1. Reducing the gene expression of HMGcoA reductase
2. Reduced gene expression of LDLR
3. Excess cholesterol is stored as cholesterol esters
What is familial hypercholesterolaemia? Which genes cause it? What does it increase the risk of?
- Autosomal dominant Genetic disease caused by genetic mutations in either of 3 genes:
1. LDLR – receptor for receptor-mediated endocytosis
2. PCSK9 – kinase enzyme that controls the recycling of LDL receptors.
3. APOB – gene for ApoB 100 which binds to the LDL receptor - Increased chance of coronary heart disease by causing a high level of LDL to accumulate in the blood.
- Estimated prevalence of 1 in 500 in the UK.
- Causes high levels of cholesterol of accumulate in the blood due to lack of receptor-mediated endocytosis of cholesterol by peripheral cells.
- Can cause heart attacks even in children with homozygous mutations.
What is high-density lipoprotein? What are its functions? Where is it produced and what protein does it contain? What happens once it starts circulating?
- Two Important functions:
1. Apoprotein exchange
2. Reverse transport pathway - HDL is produced in the liver as a pre-cursor containing mainly ApoA1 (pre – β HDL)
- Once it start circulating it collects cholesterol from other cells (through the ABCA1/G1 membrane transport protein) and esterifies it to cholesterol ester which it can exchange with other cells or lipoproteins.
- HDL transfer excess cholesterol ester to the liver by binding to scavenger receptors (SR-B1) on the surface of hepatocytes and HDL can go back to continue shuttling in the circulation.
- Liver can get rid of excess cholesterol esters in bile.
- (humans cannot metabolize cholesterol)
What happens in the endogenous pathway (LDL)?
VLDL synthesised in liver
Fatty acids cleaved off to become IDL
Fatty acids cleaved off again to become LDL, or reuptake via remnant receptor
Reuptake of LDL via LDL receptor (but not in familial hypercholesterolaemia) or a residual fraction of LDLs bind low affinity scavenger on macrophages and are phagocytised
These turn to foam cells and deposit in atherosclerotic plaques.
