chloesterol Flashcards
- What is cholesterol?
- What part of cholesterol is not hydrophobic?
steroid composed of 27 carbon atoms
composed of cyclic rings with a hydrophobic tail
Hydroxyl group at position 3
- Where is most of the cholesterol in our bodies found?
- What is a key property of cholesterol?
- Where does de novo synthesis of cholesterol occur
Cell membranes
It can increase and decrease membrane stiffness, depending on the temperature and the nature of the membrane Liver
- Name the 3 main parts in cholesterol biosynthesis
Synthesis of isopentenyl pyrophosphate (cytoplasm)
Condensation of 6 molecules of isopentenyl pyrophosphate to form squalene (cytoplasm) Cyclisation and demethylation of squalene by monooxygenases to give cholesterol (ER reactions)
- What are the 3 sources of lipids?
- Diet
- De novo biosynthesis (liver)
- Storage deposits in adipose tissue
- Where are bile salts generated and where are they stored?
- what are the two bile salts
Generated in liver
Stored in gall bladder
glycocholate
taurocholate
- What is isopentenyl pyrophosphate?
Activated isoprene which serves as a key building block for cholesterol
- What is the first step of cholesterol biosynthesis?
Condensation of 2 Acetyl-CoA molecules to form Acetoacetyl CoA
Catalysed by Beta-ketothiolase
- What is the second step of cholesterol biosynthesis?
Condensation of another acetyl-CoA with acetoacetyl-CoA to form HMG-CoA
This step is catalysed by HMG-CoA synthase
- What is the third step of cholesterol biosynthesis?
HMG CoA is reduced to generate mevalonate
Enzyme is HMG-CoA reductase
what is step 8 of cholesterol synthesis
Lanesterol reduced and 3 methyl units removed to generate cholesterol
- Which step does cholesterol itself inhibit?
It inhbits the third step (enzyme HMG-CoA reductase) in a negative-feedback system
- How are bile salts formed and what is the primary bile salt produced?
- what does it help absorption of?
- what does a lack of bile salts result in?
Breakdown of cholesterol
Glycocholate is the primary bile salt produced
fats, fat soluble vitamins (A,D,E,K)
majority of fats passing through the gut
results in steatorrhea
- How is pregenolone generated?
Cholesterol and action of enzyme desmolase
- What are the five classes of steroids?
Mineralocorticoids
Androgens Progestagens Glucocorticoids Oestrogens
- What condition comes as a result of a deficiency of Vitamin D3?
Rickets - defective bone development in children
- What is meant by Familial Hypercholesterolaemia?
Monogenic dominant trait, where the LDLR does not work
if inherit one mutant gene- cholesterol transportation is defective and cholesterol level is 2-3 times higher, Susceptible to atherosclerosis
if inherit both- serum cholesterol is 5 times higher, severe atherosclerosis and coronary infarcts may occur
- What is the general mechanism behind familial hypercholesterolaemia?
Low Density Lipoproteins (LDL) 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
- Explain the inhibition of de novo cholesterol synthesis by the liver and what drug is used.
HMG-CoA-Reductase Inhibitors (cholesterol) are a competitive inhibitor of HMG-CoA Reductase, e.g. - Lovastatin, lipitor
This prevents formation of mevalonate in step 3 of cholesterol biosynthesis
- Explain the reduction of dietary cholesterol absorption by the intestines is caused by resins?
Resins/sequestrants such as cholestyramine (brand names Questran, Prevalite) bind or sequester bile acid-cholesterol complexes
preventing their reabsorption by the intestine and can lower LDL by 15-30% and raise HDL by 3-5%
- What are the 5 main classes of lipids?
Free FAs
Triacylglycerols Phospholipids Glycolipids Steroids
- What are the 3 sources of lipids?
- Diet
- De novo biosynthesis (liver)
- Storage deposits in adipose tissue
- What is orlistat (tetrahydrolipstatin)?
- what does it do
A potent inhibitor of gastric and pancreatic lipases
Obesity treatment to render fats indigestible
reduce fat absorption by 30%, helps treat obesity
- What is the function of High Density Lipoproteins (HDLs)?
- What is the function of Low Density Lipoproteins (LDLs)?
Reverse cholesterol transport - They transport cholesterol from the peripheral tissues back to the liver for use/disposal
Transport cholesterol synthesised in liver to peripheral tissues And regulate de novo synthesis at these sites
- Why is it difficult to transport fats through the plasma?
- What do lipoproteins do?
Because plasma is an aqueous solution, however the fats have hydrophobic qualities
Transport lipids in the plasma
- What happens at elevated levels of LDL?
Atherosclerosis - hardening of arteries, increases risk of myocardial infarctions
- What are the main side effects of orlistat?
Abdominal pain, urgency to defecate, steatorrhea
- How are fatty acids and glycerol uptaken by the epithelial cells via the chylomicrons and what happens to chylomicrons after?
Chylomicrons transported around the body via lacteals and collect apoproteins from HDL
Chylomicrons have apoproteins lining the hydrophilic area of the chylomicrons The apoproteins bind to lipoprotein lipases along the epithelial cell membrane The triglycerides in the chylomicrons are broken down into fatty acids and glycerol to be taken in by the epithelial cells of the adipose and peripheral tissue Chylomicrons transfer remaining apoproteins to HDL and uptaken by liver to be reprocessed into VLDLs
- What happens to the chylomicron remnants and how do they initiate the lipoprotein transport pathways?
They are uptaken by the liver at remnant receptors
VLDL then transport FFA to adipose and peripheral tissue, and transfer apoproteins to HDL
VLDL then become IDLs
LDLs formed from IDL when cholesterol esters transferred to it from HDL
IDL taken in by liver at IDL receptors and LDLs transport cholesterol to peripheral tissue via LDL receptors HDL then takes the cholesterol transported to peripheral tissue by VLDL and LDL back to the liver via HDL receptors
what are the functions of these lipoproteins and what is their source?
chylomicrons- dietary fat transport, intestines
VLDL- endogenous transport, liver
IDL- LDL precursor, VLDL
LDL- cholesterol transport to tissues, IDL
HDL- reverse cholesterol transport, liver
which two molecules produce acetyl CoA
pyruvate, from sugars
fatty acids from fats
where do chylomicrons travel to?
where are lipoprotein lipases located?
what do they do?
from lacteal of intestine
to thoracic duct and left subclavian vein
where they enter bloodstream
capillary endothelial cells
that line tissues such as adipose, skeletal muscle and the heart
recognise apoprotein, activated to break chylomicron down
- Outline step 4 of cholesterol biosynthesis?
mevalonate undergoes a series of phosphorylation reactions at position 3 and 5, then decarboxylation to form 3-isopentenyl pyrophosphate
- Outline step 5 of cholesterol biosynthesis?
Isopentenyl PP → dimethylallyl PP via isomerisation reaction catalysed by isopentenyl PP isomerase
dimethylallyl condenses with another isopentenyl PP to form C10 compound Geranyl-PP geranyl PP condenses with another isopentenyl PP to form C15 intermediate farnesyl-PP
(just remember- isomerisation, then condensation twice with iso pentyl PP)
- Outline step 6 of cholesterol biosynthesis?
2 farnesyl-PP molecules condense to form C30 squalene plus 2 molecules of PP. Catalysed by squalene synthetase.
- Outline step 7 of cholesterol biosynthesis
- Squalene reduced in presence of O2 & NADPH to form squalene epoxide with different C=C distribution, priming molecule for carbon ring fusion
- Formation of Lanesterol through series of 1,2-methyl group & hydride shifts along chain of squalene molecule, resulting in formation of 4 rings
(Just remember cyclisation of squalene)
why are cholesterols esterized before going into a lipoprotein?
how are they esterized?
so they can be packed tighter
synthesised in the plasma
acyl chain from lecithin (phosphatidylcholine) attached to cholesterol
via LCAT enzyme (lecithin- cholesterol acyl transferase)
what is the structure of a lipoprotein?
phospholipid monolayer containing cholesterol and apoproteins
surrounding a core of cholesterol esters and triacylglycerols
outline the endocytosis of LDL?
LDL receptors bound to LDL
LDL released into cytosol
uncoats and fuses with an endosome
endosome transfers LDL to a lysosome
lysosome hydrolyse LDL so free cholesterol can be used by cells
budding off of transport vesicles containing LDLR
LDL receptor returned to the plasma membrane
