MBC - Cholesterol Flashcards
Why is cholesterol important?
It is a vital molecule of cell membranes, if signalling pathways, and acts as a precursor for many important biomolecules
How many carbon atoms are in cholesterol?
27
Describe the structure of cholesterol
4 cyclic rings fused together. Steroidal ring in planar structure and is very hydrophobic: consisting of mainly carbon and hydrogen atoms.
Where is the one hydroxyl molecule on cholesterol found?
Position 3
How much of our cholesterol is found in membranes?
90%
How does cholesterol affect membrane stiffness?
Increases or decreases stiffness depending on temperature and membrane natureq
How much dietary cholesterol do we take in a day roughly?
500mg
How do we produce cholesterol?
De novo synthesis in the liver from acetyl CoA
How much of our vital cholesterol is accounted for by diet?
none - we produce all the cholesterol we need in the liver.
What is the 1st process in cholesterol synthesis?
Synthesis of isopentenyl pyrophosphate in the cytoplasm
What is the 2nd process in cholesterol synthesis?
Condensation of the 6 isopentenyl pyrophosphate molecules to form squalene in the cytoplasm
What is the 3rd process in cholesterol synthesis?
Cyclisation and demethylation of squalene by monoxygenases to form cholesterol in the endoplasmic reticulum.
What is the 1st step in part 1 of synthesis?
Acetyl CoA is joined with another acetyl CoA to form Acetoacetyl CoA via B-ketothiolase, losing a CoA.
What is the 2nd step in part 1 of synthesis?
Acetoacetyl CoA is joined with another acetyl CoA to form 3-hydroxy 3-methylglutaryl CoA (HMG-CoA) via HMG-CoA synthase, with the addition of water and loss of CoA.
What is the 3rd step in part 1 of synthesis?
HMG-CoA is reduced via HMG-CoA reductase to form mevalonate, with the oxidation of NADPH to NADP+ +CoA.
How is HMG-CoA reductase controlled?
Mevalonate, cholesterol and bile salts can all inhibit the enzyme therefore act to negatively inhibit the enzyme and avoid overproduction of cholesterol.
What is the 4th (final) step in part 1 of synthesis?
Mevalonate undergoes sequential phosphorylation at positions 3 and 5 followed by decarboxylation to form 3-isopentenyl pyrophosphate.
What is the 1st step of part 2 in synthesis?
pentenyl pyrophosphate is converted to dimethylallyl pyrophosphate in an isomerisation reaction.
What is the 2nd step of part 2 in synthesis?
dimethylallyl pyrophosphate undergoes 2 sequential condensation reaction in which 2 pentenyl pyrophosphate molecules are added to give farsenyl pyrophosphate.
What is the 3rd (final) step of part 2 in synthesis?
Farsenyl pyrophosphate condenses with another farsenyl pyrophosphate molecule to form squalene and two pyrophosphate molecules, under squalene synthetase.
What is the 1st step of part 3 in synthesis?
Squalene is reduced to squalene epoxide using NADPH which is oxidised to NADP+ and H2O, via squalene monoxygenase.
What is the 2nd step of part 3 in synthesis?
Squalene epoxide is catalysed into lanesterol via squalene epoxide lanesterol cyclase.
What is the 3rd (final) step of part 3 in synthesis?
Lanesterol is subsequently reduced and demethylated to form cholesterol
How many discrete steps does it take to convert lanesterol to cholesterol?
19
How many methyl groups are removed from lanesterol to convert it to cholesterol?
3
Give three examples of how cholesterol’s versatility is shown.
Bile salts
Vitamin D
Steroid hormones
Bile salts are a major product of cholesterol, how much of synthesised cholesterol contributes to bile salts?
About half of the 800mg of cholesterol produced by the liver.
What is the primary bile salt from cholesterol break down?
Glycocholate
What is the other bile salt produced for cholesterol breakdown?
Taurocholate
What is the main feature of bile salts that allows them to emulsify fats?
They have both hydrophobic and hydrophilic properties.
What is the main precursor for all 5 steroidal hormone classes?
Pregnenolone
What are the 5 classes of steroid hormone?
Oestrogens Androgens Progesterones Glucocorticioids Mineralocorticoids
What converts cholesterol to pregnenolone?
Desmolase
What is vitamin D?
Collective term of hormones that are required for the intestinal absorption of ions needed for bone regulation
What are the ions needed for bone development?
Calcium
Phosphate
Magnesium
How do people with a Western diet get most of their vitamin D?
Sunlight, as the Western diet typically contains low vitamin D levels
How does UV light causes the synthesis of vitamin D from cholesterol?
UV light facilitates the conversion of 7-dehydrocholesterol to previtamin D3. Previtamin D3 is then converted to vitamin D3 (cholecalciferol) which is ultimately converted to calcitriol (1,25-dihydroxycholecalciferol)
What is calcitriol?
The most active vitamin D metabolite and plays a key role in calcium metabolism
What does calcitriol bind to?
It acts as a steroid hormone so binds to Vitamin D responsive elements (VDREs) in the promoter region of the target gene to influence bone metabolism.
What is caused by childhood deficiency of vitamin D3
Rickets.
What is familial hypercholesterolaemeia (FH)?
Monogenic dominant trait that results in cholesterol transport being defective.
How are heterozygotes for FH affected?
They have serum cholesterol 2-3 times higher than a normal person.
They are at risk to atherosclerosis in middle age.
How are homozygotes for FH affected?
This is sever FH, serum cholesterol may be around 5 times higher than normal
They are at risk to atherosclerosis or myocardial infarction during adolescence.
How was the mechanism for FH discovered?
By culturing the fibroblasts of healthy and affected individuals.
What was observed in severe FH patients?
Patients lacked functional LDL receptors (LDLRs), due to mutations in several domains of LDLRs.
What else has been reported due to mutations in LDLR domains?
Receptor expression
LDL binding
LDLR endocytosis
Recycling.
What are the 2 main strategies for managing hypercholesterolaemia?
Inhibition of de novo synthesis in the liver
Reduction of dietary cholesterol absorption in the liver
What is cholestyramine?
Resin/sequestrant that binds to bile acid-cholesterol complex to prevent its absorption into the liver.
Are sequestrants or resins effective?
Yes - they can lower LDLs by 15-30% and raise HDLs by 3-5%.
What is lovastatin?
Statin or HMG-CoA reductase inhibitor. Competitively inhibits the enzyme to prevent the formation of cholesterol early on.
