Cholesterol Flashcards
What three primary are fats derived from?
The diet
De novo biosynthesis - liver
Storage depots in adipose tissue
Where are bile salts generated and stored? What do they do?
Generated by liver and stored in gallbladder
During digestion they pass from the bile duct into the intestine
Emulsify fats in the intestine aiding their digestion and absorption of fats and also that of fat-soluble vitamins A, D, E and K
What does a lack of bile salts lead to?
Majority of fat passes through the gut undigested and unabsorbed
This leads to steatorrhoea
What is orlistat/tetrahydrolipstatin?
Inhibitor of gastric and pancreatic lipases
chemically synthesised derivative of lipstatin (product of streptomyces toxytricini)
Reduces fat absorption by 30% which is then excreted faecally
Name the five lipoproteins and their sources
Chylomicrons - intestines
VLDLs - liver
IDL - VLDL
LDL - IDL
HDL - liver
Role of chylomicron?
Dietary fat transport
Role of VLDL?
Endogenous fat transport
Role of IDLs and LDLs?
IDLs - intermediate LDL precursor
LDL- cholesteron transport
Role of HDLs?
Reverse cholesterol transport
What do chylomicrons acquire from HDLs when released into the blood stream?
Apoproteins
Where do chylomicrons travel from and to, to get to the bloodstream?
From the lacteals of intestine to the thoracic duct and left subclavian vein where they enter the blood stream
Where is lipoprotein lipase found and what does it bind to?
Located on the capillary endothelial cells lining adipose tissue heart and skeletal muscle
Bind to apoproteins cleaving the chylomicron
What are the properties of the shell and core of a chylomicron?
Hydrophillic outer shell
Hydrophobic core
What is cholesterol and what does it do?
Cholesterol is a steroid
It increases or decreases membrane stiffness, depending on temperature and nature of membrane
Where is most of the cholesterol in our body found?
More than 90% in cell membranes
What is dietary uptake of cholesterol?
How are physiological requirements for cholesterol met?
0.5g/day
Supplied by the liver by de novo synthesis of cholesterol from acetyl-CoA
What are the three main parts of the cholesterol synthesis pathway and where do they occur?
- synthesis of isopentenyl pyrophosphate, activated isoprene unit - key building block (cytoplasm)
- Condensation of six molecules of isopentenyl pyrophosphate to form squalene (cytoplasm)
- cyclisation and demethylation of squalene by monooxygenase to give cholesterol (ER)
What are four steps of isopentenyl pyrophosphate synthesis?
- Condensation of 2 Acetyl-CoA molecules to form acetoacetyl CoA using β=ketothiolase
- further condensation by acetyl-CoA via HMG-CoA synthase to form HMG-CoA
- HMG-CoA reduced to form mevalonate via HMG-`CoA reductase
- Mevalonate sequentially phosphorylated at hydroxyl groups positions, then decarboxylated to form 3-isopentenyl pyrophosphate
enzymes: mevalonate kinase, phosphomevalonate kinase, kinase, phospho mevalonate decarboxylase
What is HMG-CoA reductase under negative feedback control by?
End product cholesterol, bile salts and the mevalonate intermediate
What does the isoprene unit do?
Confers lipophilicty to biomolecules - gives them affinity for lipid bilayers
What two steps produce squalene from the isoprene unit?
- Dimethylallyl pyrophosphate can be produced from isopentyl pyrophosphate via isopentenyl isomerase
This then condenses with a unit of isopentenyl-pp to form Geranyl pyrophosphate (C10 compound)
Third isopentenyl-PP molecule is added to form fernesyl pyrophosphate (C15 intermediate)
- Two farnesyl pyrophospate molcules condense via squalene synthase to form C30 squalene and two molecules of pyrophosphate
What are the three steps in which squalene is cyclised to cholesterol?
1, squalene is reduced in the presence of O2 and NADPH to form squalene epoxide via squalene epoxidase
- enzyme squalene epoxide lanosterol-cyclase catalyses formation of lanosterol - formation of four rings occurs
What are the three steps in which squalene is cyclised to cholesterol?
1, squalene is reduced in the presence of O2 and NADPH to form squalene epoxide via squalene epoxidase
- enzyme squalene epoxide lanosterol-cyclase catalyses formation of lanosterol - formation of four rings occurs
- Lanosterol is subsequently reduced and demethylated to generate cholesterol
How is pregnenolone generated from cholesterol?
By the action of the enzyme desmolase
What are the 5 classes of steroid hormones from pregnenalone?
Progestogens
Glucocorticoids
Mineral corticoids
Androgens
Estrogens
What are bile salts?
Major breakdown products of cholesterol and account for half of the 800mg of cholesterol made each day
Explain the anatomy of a lipoprotein?
phospholipid monolayer containing cholesyerol and apoproteins
Surrounds a core of cholesterol esters and triacylglycerols
How are cholesterol esters formed?
Synthesised in plasma from cholesterol and the acyl chain of phospahtidylcholine (lecithin) via lecithin:cholesterol acyltransferase (LCAT)
What is good cholesterol and why?
HDL - take cholesterol from peripheral tissues back to the liver for use or disposal (reverse cholesterol transport) -
lower total serum cholesterol
Whats bad cholesterol and why?
LDLs - prolonged elevation leaads to astherclerosis
Transport cholesterol synthesisded in liver to peripheral tissues with more than 40% of their weight made up of cholesterol esters
What is familial hypercholesterolaemia?
Monogenic dominant trait
Cholesterol transportation is defective and cholesterol level is 2-3 times higher
Susceptible to atherosclerosis in middle age
What is the general mechanism behind familial hypercholesterolaemia?
LDLs give rise to a form of cholesterol called LDL-derived cholesterol
This form is usually taken up by LDL receptors (LDLR)
Patients with severe FH lacked functional LDLRs along their fibroblasts
So they are unable to take up the the LDL-derived cholesterol
What are the two ways to control hypercholesterolaemia?
Resins/sequestrants - such as cholestyramine bind to sequester bile acid-cholesterol complexes preventing their reabsorption by the intestine and can lower LDL by 15-30% and raise HDL by 3-5%
HMG-CoA reductase inhibitors- competitive inhibitor of HMG-CoA Reductase aka statins e.g. - Lovastatin, lipitor
This prevents formation of mevalonate in step 3 of cholesterol biosynthesis
What are the two ways to control hypercholesterolaemia?
Resins/sequestrants - such as cholestyramine bind to sequester bile acid-cholesterol complexes preventing their reabsorption by the intestine and can lower LDL by 15-30% and raise HDL by 3-5%
HMG-CoA reductase inhibitors- competitive inhibitor of HMG-CoA Reductase aka statins e.g. - Lovastatin, lipitor
This prevents formation of mevalonate in step 3 of cholesterol biosynthesis
What are the two ways to control hypercholesterolaemia?
Resins/sequestrants - such as cholestyramine bind to sequester bile acid-cholesterol complexes preventing their reabsorption by the intestine and can lower LDL by 15-30% and raise HDL by 3-5%
HMG-CoA reductase inhibitors- competitive inhibitor of HMG-CoA Reductase aka statins e.g. - Lovastatin, lipitor
This prevents formation of mevalonate in step 3 of cholesterol biosynthesis
Explain the process of receptor mediated endocytosis of LDL
LDL binds to LDL receptors
Endocytosis of clathrin coated vesicle
Uncoating
Fusion with endosome
TRansfer to lysosome > free cholesterol released
Budding off of transport vesciles
return of LDL receptors to plasma membrane
Explain the process of receptor mediated endocytosis of LDL
LDL binds to LDL receptors
Endocytosis of clathrin coated vesicle
Uncoating
Fusion with endosome
TRansfer to lysosome > free cholesterol released
Budding off of transport vesciles
return of LDL receptors to plasma membrane
