Lipids 4 Flashcards
What makes cholesterol useful?
That it’s Janus-faced and has insolubility in water
Sources of cholesterol?
- Diet eg eggs, liver, fish
- De novo synthesis (adults on low cholesterol diet synthesis around 800mg cholesterol per day), cells can’t degrade steroid nucleus, excreted by the liver (in bile), consume it biochemically
What’s the major site of cholesterol synthesis?
Liver (needs to be tightly regulated)
Where are all 27 carbons of cholesterol derived from?
Acetyl CoA in 3 stages
3 stages synthetic process that cholesterol gains 27 carbons?
- Synthesis of isopentenyl pyrophosphate, an inactivated isoprene that is the key building block of cholesterol
- Condensation of 6 molecules of isopentyl pyrophosphate to form squalene
- The cyclisation of squalene in an “outstanding reaction” and the tetracyclic product is subsequently converted into cholesterol
Where do the three stages of cholesterol synthesis located?
1= cytoplasm 2,3= endoplasmic reticulum
What’s the committed step of cholesterol formation?
Synthesis of mevalonate
What catalyses the synthesis of mevalonate?
HMG-CoA reductase
What is the intermediate in the first step of cholesterol synthesis?
HMG-CoA (from acetyl CoA and acetoacetyl CoA)
Four ways HMG COA reductase controlled?
- Rate of synthesis
- Rate of translation
- Rate of degradation
(1-3 alter the amount of enzyme more than 200 fold) - Phosphorylation of the reductase reduces its activity
What are potent competitive inhibitors of HMG-CoA reductase?
Lovostatin and related compound
What is another method on inhibiting cholesterol levels?
Inhibiting intestinal reabsorption of bile salts (bile salts ate cholesterol derivatives that promote the absorption of dietary cholesterol and dietary fats)- this is the oral administration of positively charged polymers (eg cholestyramine) that bind negatively charged bile salts
What transports cholesterol throughout the organism?
Lipoproteins
What are lipoproteins comprised of?
A core of hydrophobic lipids surrounded by a shell of more polar lipids and proteins
What can lipoprotein particles shift between?
Classes as they release or pickup cargo, thereby changing their density
What is the purpose of low- density lipoprotein?
B100, cholesterol transport
What’s the purpose of high-density lipoprotein?
Reverse cholesterol transport
What are the two roles of the apoproteins (protein components of macro molecular aggregates)?
Solubilise hydrophobic lipids
Contain cell-targeting signals
What plays a central role in cholesterol metabolism?
Low-density lipoproteins
What’s a primary source of cholesterol from cells outside the liver and intestine that don’t make a lot of it?
Plasma (not de novo synthesis)
Primary source of cholesterol transport?
LDL
Steps of receptor mediated endocytosis?
- B100 (apolipoprotein) binds to LDL receptor
- LDL particle complex is internalised by endocytosis
- Endosome is acidified (proton pump)
Causes receptor to release LDL cargo- some receptor returns to cell surface, some is degraded - Endosome fuses to lysosomes, protein components hydrolysed to free amino acids. Cholesterol esterols hydrolysed to release free cholesterol (membrane biosynthesis, re-esterified, stored inside cell- must be ester)
How does the LDL receptor relinquish its cargo on entering the cell?
In its extended or open state it binds LDL
In its closed state it releases the LDL in endosome and decreases pH of endinsmbe
What does the absence of the LDL receptor lead to?
Hypercholesterolaemia and atherosclerosis
What is familial hyoercholesterolaemia?
When cholesterol is deposited in various tissue because the high concentration of LDL cholesterol in the plasma- molecular effect in most cases is an absence or a deficiency of functional receptors for LDL
What is homozygote in familial hypercholesterolaemia?
No functional LDL receptors
Most die of severe coronary heart disease in childhood
What is heterozygote form of familial hypercholesterolaemia??
Half the normal number of LDL receptors
Premature cardiovascular disease in 30s or 40s
What does one class of mutations that results in familial hypercholesterolaemia do?
Generates receptors that are reluctant to give up LDL cargo
What do 50% of FH mutations do?
Disrupts the open/closed state conversion
What does the FH mutation of failure to disrupt the open/closed state interconversion do?
Results in failure of the receptor to release the LDL particle and loss of the receptor by degradation
What are some important derivatives of cholesterol?
Vitamin D, bile salts, steroid hormones
What are bile salts?
- polar derivatives of cholesterol
- highly effective detergents
- are released into the small intestine and solubilise dietary lipids
What is a precursor to the 5 major classes of steroid hormones?
Cholesterol
