Cholesterol Synthesis and Lipoprotein Transport Flashcards
What is the structure of cholesterol?
27 carbons, 4 rings, planar, one side hydrophobic, one side hydrophilic (because of hydroxyl group at carbon 3)
What are the properties of cholesterol?
waxy, steroid metabolite that is insoluble in water
Where is cholesterol commonly found in the body?
In atherosclerotic plaques and gall stones
Where is cholesterol made?
In the liver
What are the three fates of cholesterol?
Stored in the liver, bile or in membranes
How is is stored in the liver?
As a cholesteryl ester (enzyme ACAT removed hydroxyl group)
Why is cholesterol required in membranes?
Because phospholipid have cis bond kinks making the membrane too fluid - 8% cholesterol fills these gaps and makes the membrane the right level of solidness at 37 degrees
How is cholesterol synthesised?
Acetyl CoA goes to acetoacetyl CoA which goes to HMG CoA which goes to mevalonic acid (using 2NADPH and HMG-CoA reductase), mevalonic acid goes to cholesterol
What is the feedback mechanism in the pathway?
Cholesterol negatively feedbacks to HMG CoA reductase
What are the intermediates in the conversion of mevalonic acid to cholesterol?
Squalene and isoprene
Where does acetyl CoA come from?
Mitochondria - from glucose or fatty acid metabolism
How does acetyl CoA get from the mitochondria to the cytosol?
Converts to citrate via the Krebs cycle which can pass through the membrane and then the reverse Krebs cycle is used to convert it back to acetyl CoA
What are lipoproteins?
A phosopholipid monolayer sphere with a hydrophobic inside filled with cholesterol and triacylglyerols
What kinds of lipoproteins are there?
chylomicrons, VLDL, LDL and HDL
What are chylomicrons?
A lipoprotein package formed from dietary fats that allows them to be transported in circulation
What is apoB-100?
The pure protein part of the lipoprotein - recognised by receptors on the liver
Which lipoprotein contains the most cholesterol?
LDL
Which lipoprotein contains the most triacylglycerols?
chylomicrons
What lipoprotein is ApoA-I associated with?
HDL
What is the role of ApoA-I?
activates the enzyme LCAT
What lipoproteins in ApoC-II associate with?
chylomicrons, VLDL, HDL
What is the role of ApoC-II?
Activates the enzyme lipoprotein lipase so that tissues can use fat as an energy source
Which lipoprotein is the scavenger?
HDL
Which lipoprotein is the donor?
LDL
Where do VLDL come from?
The liver
What happens to chylomicrons after they have been stripped of their free fatty acids in circulation by tissues with ApoC-II?
The remnants are transported back to the liver to be recycled
What happens to VLDLs after they have been stripped of their free fatty acids in circulation by tissues with ApoC-II?
The remnants (also called IDL) are either transported back to the liver for recycling or can be converted to LDL
Where does LDL go?
To extrahepatic tissue (e.g. the arteries) to deposit cholesterol
Where do HDL precursors come from?
The liver and intestine
What does HDL do?
Goes to the cholesterol deposits made by LDL and scavenge the cholesterol and take it back to the liver to be recycled
What is the role of LCAT?
It is an enzyme in the plasma activated by ApoA-I that converts cholesterol into an ester to become part of HDL
What is the role of ACAT?
It is an enzyme in the liver that converts cholesterol into an ester to from a VLDL
What is the structure of HDL?
Two circular protein molecules surround cholesterol and phospholipids
What is the upper limit of cholesterol recommended by the national heart foundation?
5.5mmol/L
How is atherosclerosis formed?
LDL accumulates in an artery wall, endothelial cells in the artery react by displaying adhesion molecules, white cells invade the tissue and secrete inflammatory mediators, macrophages digest LDLs and become engorged with cholesterol and become foam cells, fibrous tissue develops to trap the foam cells, foam cells produce tissue factor and if the fibrous cap breaks a blood clot can form
What is familial hypercholesterolaemia?
An inherited dominant disorder of mutations in the LDL receptor - affects 1/500 in the heterozygous form and 1/million in the homozygous form
What are xanthomas?
Cholesterol deposits - waxy plaques beneath the skin in untreated familial hypercholesterolaemia
How is familial hypercholesterolaemia treated?
With HMG CoA reductase inhibitors - statins
Who won the nobel prize for the development of statins?
Michael Brown and Joseph Goldstein in 1985
What is an adverse effect of statins?
Depleted Q10
