7. Cholesterol Flashcards
Cholesterol
Steroid
Alters membrane stiffness depending on temperature and nature of membrane
Changes interactions with cytoskeleton
Where is cholesterol synthesised and what from?
Liver
From Acetyl-CoA
What are the 3 main parts of cholesterol biosynthesis?
Synthesis of isopentyl pyrophosphate from acetyl-CoA
Condensation of 6 molecules of isopentyl pyrophosphate to form squalene
Cyclisation and demethylation of squalene by mono-oxygenates to give cholesterol
What steroid hormone precursor is derived from cholesterol and what enzyme creates this?
Pregnenolone
Enzyme: Desmolase
What Vitamin is synthesised from cholesterol?
Vitamin D
Where are bile salts generated and stored?
Generated in Liver
Stored in Gallbladder
Where do bile salts pass during digestion and what do they do?
From bile duct into intestine
Emulsify fats in intestine, aiding digestion and absorption of fats and fat-soluble vitamins (A, D, E, K)
What do bile salts have and what happens when they form micelles?
Hydrophobic face and a hydrophilic face.
When they form micelles, their hydrophilic faces face away from triacylglycerols (TAGs) and their hydrophobic faces point towards TAGs.
What does a lack of bile salts result in?
Passage of fat through the gut undigested and unabsorbed causing steatorrhea (fatty stool).
What are the major breakdown products of cholesterol?
Bile salts
What breakdown products of cholesterol are used as bile salts?
Taurocholate and Glycocholate
What are Lipid rafts?
Fluctuating assemblies of cholesterol and sphingolipids within a plasma membrane.
What are Hedgehog signalling proteins (N-Hh) covalently attached to?
Cholesterol to limit diffusion within tissue to allow for successful limb formation in embryogenesis
What do Lipid rafts do?
Organise processes such as cellular signalling by localising key proteins like cell surface receptors
Why is transportation of lipids difficult and what is the solution to this?
Lipids are insoluble in aqueous solutions
SOLUTION: package within lipoproteins
What do the phospholipid monolayers of lipoproteins consist of?
Phospholipids
Cholesterol
Apoproteins
What is contained in the core of a lipoprotein?
Cholesteryl ester
Triacylglycerols
What do apoproteins on lipoproteins allow?
Particle to be recognised by tissue
Where are Cholesterol esters synthesised and what from?
In plasma
From cholesterol and acyl chain of phosphatidylcholine (Lecithin)
What catalyses the formation of Cholesterol esters?
Lecithin cholesterol acyltransferase (LCAT)
How does LCAT work?
More hydrophobic than cholesterol therefore they pack more tightly into the lipoprotein core
What can Acyl CoA cholesterol acyltransferase (ACAT) generate?
Cholesterol esters from a long chain fatty acyl CoA species.
What type of enzyme is ACAT and when does it act on cholesterol?
ACAT is an intracellular enzyme
Acts on cholesterol which has been taken in by endocytosis.
How are lipoproteins categorised?
ACCORDING TO THEIR DENSITY
What are the categories of lipoprotein?
Chylomicrons (CM) Very Low Density Lipoproteins (VLDL) Intermediate Density Lipoproteins (IDL) Low Density Lipoproteins (LDL) High Density Lipoproteins (HDL)
Each type of lipoprotein has a varying apoprotein component, what does this allow?
Allows them to be recognised by different cell types
When fats are absorbed how are they packaged and where do they travel?
Packaged into chylomicrons (CMs)
Travel in lymphatics from intestines to thoracic duct and subclavian vein where they enter blood stream
Where is lipoprotein lipase found and what does it do?
It is found in capillary endothelial cells
Catalyses hydrolysis of triacylglycerols (in CMs) to glycerol and fatty acids
Once lipoprotein lipase has catalysed hydrolysis of triacylglyerols, where are the products used?
Fatty acids are used in beta-oxidation
Glycerol is returned to liver for use in gluconeogenesis
What plays a key role in activating lipoprotein lipase?
Apoprotein C-II of CM
What type of cholesterol are HDLs?
Good cholesterol
What is the function of HDLs?
To take cholesterol from peripheral tissues back to liver for use or disposal (reverse cholesterol transport).
What do HDLs help to lower?
Total serum cholesterol
What type of cholesterol are LDLs?
Bad cholesterol
What does prolonged elevation of LDL levels lead to?
Atherosclerosis (hardening of the arteries)
What do LDLs do?
Transport cholesterol synthesised in liver to peripheral tissues
> 40% of their weight made up of cholesterol esters.
What type of disease is familial hypercholesterolaemia (FH)?
Inherited monogenic dominant
What are the clinical features of familial hypercholesterolaemia?
High risk of severe atherosclerosis and coronary infarction in adolescence
Heterozygotes with FH serum cholesterol levels
2-3X higher than normal
Homozygotes with FH serum cholesterol levels
5X higher than normal
What mutation causes FH?
Mutation of LDLR (LDL receptor)
Can’t take up LDLs
Describe Receptor mediated endocytosis of LDL
LDLRs receive LDLs and send them to the early endosome
Here, LDLRs are recycled back to plasma membrane
LDLs are transferred to lysosomes where they’re degraded to give free cholesterol
How do statins reduce the accumulation of cholesterol? Give an example
Statins are HMG-CoA Reductase inhibitors
Competitive inhibitors stop/reduce cholesterol production
E.g. Lipitor
What do Resins and Sequestrants do?
Bind or sequester bile acid-cholesterol complexes preventing their reabsorption by the intestine.
Lowers LDL levels
Raises HDL levels
In the biosynthesis of cholesterol, where does synthesis of isopentyl pyrophosphate occur?
Cytoplasm
In the biosynthesis of cholesterol, where does synthesis of squalene occur?
Cytoplasm
In the biosynthesis of cholesterol, where does the ultimate synthesis of cholesterol occur?
Endoplasmic reticulum
