Cholesterol Flashcards
What is cholesterol?
a steroid composed of 27 carbon atoms
- composed of cyclic rings (planar) with a hydrophobic tail
Is cholesterol hydrophobic?
Apart from the hydroxyl group at position 3
- consisting only of carbon and hydrogen atoms
What is the role of cholesterol?
vital component of cell membranes (90 % of cholesterol in body is found there)
What is a key property of cholesterol?
it can increase and decrease membrane stiffness, depending on the temperature and the nature of the membrane
How is cholesterol obtained?
dietary uptake v. small: 500mg/day
- most supplied by the liver through de novo synthesis of cholesterol from acetyl-CoA
What are the main 3 steps in cholesterol synthesis?
- Synthesis of isopentenyl pyrophosphate
- Condensation
- Cyclisation and demethylation
What is isopentenyl pyrophosphate?
an activated isoprene which is a key building block (cytoplasmic reactions).
What happens in the condensation step of cholesterol synthesis?
Condensation of six molecules of isopentenyl pyrophosphate to form squalene (cytoplasmic reactions)
What happens in the Cyclisation and demethylation step of cholesterol synthesis?
Cyclisation and demethylation of squalene by monooxygenases to give cholesterol (ER reactions)
What is step 1 of cholesterol biosynthesis?
2 x acteyl-CoA condense to form acetoacetyl CoA
enzyme: β-KETOTHIOLASE
and one CoA is lost
What is step 2 of cholesterol biosynthesis?
acetoacetyl CoA + acetyl CoA –(H2O –> CoA)–> 3-hydroxy-3-methylglutaryl CoA (HMG-CoA)
enzyme: HMG-CoA SYNTHASE
What is step 3 of cholesterol biosynthesis?
HMG-CoA is reduced to generate mevalonate
enzyme: HMG- CoA REDUCTASE
in the process: 2 NADPH + 2 H+ –> 2 NADP+ + CoA
What controls HMG-CoA?
under the control of negative feedback by:
end product- cholesterol
intermediate mevalonate
bile salts
What is step 4 of cholesterol biosynthesis?
3 phosphorylations from mevalonate to 5-pyrophospho-mevalonate (3 ATP converted to ADP)
one carboxylation from 5-pyrophospho-mevalonate to 3-isopentenyl pyrophosphate (loosing CO2 and Pi)
What is the activated isoprene unit useful for?
building block for further synthesis
What is the role of isoprene?
confers lipophilicity to molecules
How do molecules get affinity for lipid bilayers?
lipid modifications: prenylation
What is step 5 of cholesterol biosynthesis?
- dimethylallyl is produced by isomerization from isopentyl PP
- this condenses with a unit of isopentenyl-PP to produce geranyl-PP (10C)
- a third isopentenyl-PP is added to form farnesyl-PP (15C)
What is step 6 of cholesterol biosynthesis?
2 x farnesyl-PP molecules condense to form squalene (30C) + 2 pyrophosphate + NADP+ + H+
What is step 7 of cholesterol biosynthesis?
- squalene reduced to squalene epoxide in the presence of O2(–> H2O) and NADPH [primes molecule for ring fusion]
- formation of lanosterol (4 rings)
What is step 8 of cholesterol biosynthesis?
lanosterol is reduced and 3 methyl units removed to generate cholesterol
What are bile salts ?
the major breakdown products of cholesterol
converted into glycocholate and taurocholate
what is the role of bile salts?
key in emulsifying dietary fats due to their hydrophobic and hydrophillic faces
What are streriods?
The precursor pregnenolone is generated from cholesterol by the action of the enzyme desmolase. All five classes of steroid hormones come from pregnenolone
What are the 5 classes of steroids?
Progestagens, glucocorticoids, mineralocorticoids, androgens and oestrogens
What is vitamin D?
a collective term for a group of steroids which are vital for the intestinal absorption of important ions needed for bone development, namely calcium, phosphate and magnesium
What is our main source of vitamin D?
activity of UV light upon 7-dehydrocholesterol in the epidermis of the skin
What is calcitriol?
the most active vitamin D metabolite and plays a key role in calcium metabolism
- It functions as a steroid hormone, binding to vitamin D response elements (VDREs) in the promoter of target genes and inducing key genes involved in bone metabolism
What does a deficiency in vitamin D3 lead to?
rickets, a defect of bone development in children.
What is Familial hypercholesterolaemia (FH)?
monogenic dominant trait in which cholesterol transportation is defective
– more susceptible to atherosclerosis
What happens when a person has Familial hypercholesterolaemia (FH)?
- xanthomas lying superficially over the knees, the wrists, and hands arise from the scavenging of plasma LDL-derived cholesterol by macrophages of the skin
- Deposition of LDL-derived cholesterol in the coronary arteries. This can lead to their occlusion and myocardial infarction
What is cholesterol taken up by on the cell surface ?
specific receptor molecules- the LDL receptor (LDLR)
What do FH patients lack?
functional LDLRs
A variety of mutations in the low density lipoprotein receptor (LDLR) give rise to the condition known as familial hypocholesterolaemia. Which functions do LDLR mutations affect directly ?
Mutations in the LDLR gene can affect LDLR expression, LDL binding, LDLR expression and LDLR recycling
How can FH be controlled?
Inhibition of de novo cholesterol synthesis by the liver,
or the reduction of dietary cholesterol absorption by the intestines
[HMG-CoA reductase inhibitors-liver and resins- intestine]
What do resins do?
bind or sequester bile acid-cholesterol complexes preventing their reabsorption by the intestine
- lower LDL by 15 -30% and – - raise HDL by 3 - 5%.
Examples of resins?
Cholestyramine (brand names: Questran, Prevalite)
Examples of HMG-CoA-Reductase inhibitors ?
Lipitor (Pfizer), Crestor (Astra Zeneca), lovastatin
