2.5 Cholesterol Flashcards
What are the three primary sources of fats?
- The diet
- De novo biosynthesis (liver)
- Storage depots in adipose
What breaks down dietary fats?
Lipases
What are needed to solubilize dietary fats?
Bile acids
What does a lack of bile acids result in?
Steatorrhea (Fatty stool) - this is because majority of fat passes throuhg the gut undigested and unabsorbed
What produces bile salts?
Liver
What do bile salts do in digestion?
They emulsify fats in the intestine and aid the digestion of fat soluble vitamins (A, D, E and K)
What is Orlistat?
A potent inhibitor of gastric and pancreatic lipases
What is the main side effect of Orlisats?
Steatorrhea
what do lipoproteins do?
Transport lipids in the plasma
Where are chylomicrons produced and what is their role?
Intestine - dietary fat transport
Where are digested dietary products absorbed?
By the enterocytes that line the brush border of the small intestine
Where do chylomicrons acquire apoproteins from?
From HDL following release into the blood stream
How do chylomicrons enter into the blood stream?
Travel from the lacteals of the intestine into the thoracic duct and into the left subclavian vein from which they enter into the blood stream
What is the primary role of cholesterol in the body?
Maintenance of cell membrane integrity - can increase or decrease the stiffness depending on the temperature and nature of the membrane
How are all the physiological requirements for cholesterol met?
They are supplied by the liver thorugh the de novo synthesis of cholesterol from Acetyl CoA
What is the first step in cholesterol biosynthesis?
Condensation of 2 acetyl CoA into 1 acetoacetyl CoA
Catalysed by beta-ketothiolase
What is the second step of cholesterol biosynthesis?
Condensation of another Acetyl-CoA molecule to form HMG-CoA
Catalysed by HMG-CoA Synthetase
What is the third step in cholesterol biosynthesis?
HMG-CoA is reduced to generate mevalonate
Catalysed by HMG-CoA reductase
What enzyme is used to convert HMG-CoA into Mevalonate?
HMG-CoA Reductase
Describe how HMG CoA reductase is under negative feedback?
HMG-CoA reductase is inhibited by the end product cholesterol, bile salts and mevalonate
What is the fourth step in cholesterol biosynthesis?
Mevalonate undergoes sequential phosphorylation at the hydroxyl groups at position 3 and 5
Then decarboxylation to form 3-isopentenyl pyrophosphate
What is the fifth step in cholesterol biosynthesis?
Isomerisation of isopentenyl PP into dimethylallyl PP
Condensation with isopentenyl PP to form C10 geranyl PP
Adding another isopentenyl PP to form C15 farnesyl PP
What is the sixth step in cholesterol biosynthesis?
2 C15 farnesyl PP condense to form C30 squalene and 2 pyrophosphates
What is the seventh step in cholesterol biosynthesis?
Squalene is reduced to squalene epoxide in presence of O2 and NADPH
Squalene epoxide lanosterol-cyclase catalyses formation of lanosterol
What is the eighth step in cholesterol biosynthesis?
Lanosterol is reduced and 3 methyl groups are removed, forming cholesterol
Why is ubiquinone confined to the inner membrane of the mitochondria?
Because it has lipophilic properties due to the isoprene unit
What is cholesterol the precursor of?
Pregnenolone
Describe the synthesis of Vitamin D from cholesterol?
7-dehydrocholesterol in the skin under UV is converted into Pre Vitamin D then cholecalciferol
Cholecalciferol then undergoes hydroxylation using 25-Hydroxylase to form 25-OH Cholecalciferol
1-alpha hydroxylase from the kidney produces 1,25(OH)2 Cholecalciferol (CALCITRIOL)
What does calcitriol bind and induce?
Vitamin D response elements in promoter or target genes
Induces key genes in bone metabolism
What are the names of the bile salts which are synthesized from cholesterol?
Cholesterol is converted by a series of reactions into the primary bile salt glycocholate and also taurocholate
What does a deficiency of Vitamin D3 in childhood lead to?
Rickets
What is HDL?
Cholesterol which takes cholesterol away from the peripheral tissue back to the liver for use or disposal
Helps to lower total serum choleterol
What does prolonged levels of LDL lead to?
Atherosclerosis
What do LDLs do
They transport chlesterol which has been made in the liver to the peripheral tissues - more than 40% weight is cholesterol esters
What is reverse cholesterol transport?
When cholesterol is transported back to the liver by the actions of HDL
Describe the pathophysiology of hypercholesterolaemia?
Patients lack functional LDL receptors
How is hypercholesterolaemia treated?
Using resins and HMG-CoA reductase inhibitors
What is an example of a HMG-CoA-Reductase inhibitor?
Statin
How do resins work as a medication to contain hypercholesterolaemia?
Resins bind or sequester bile acid-cholesterol complexes preventing their reabsorption by the intestine
What do fats need in order to be made soluble?
They need to be emulsified by bile
What does the emulsification of large fat droplets result in?
The formation of micelles
How do emulsified fat droplets form micelles?
Pancreatic lipase breaks down the triglycerides which have been emulsified into FFAs and monoglycerides
Once pancreatic lipases have digested the emulsified fats, what happens next?
The free fatty acids and monoglycerides leave the micelle and enter into the enterocytes of the small intestine
What happens to FFAs and MGs in the enterocytes of the mall intestine?
They reform triglycerides
What forms inside the golgi of the enterocytes?
The fatty triglyceride globules combine with proteins to form chylomicrons
Once the chylomicrons are extruded from the enterocyte what happens to them?
They enter into a lacteal and lymph in the lacteal transports chylomicrons away from the intestine
After the chylomicron has left the enterocyte of the small intestine, what happens to it on the way to the liver?
The chylomicron starts making its way to the liver and picks up apoproteins from HDL
What is the benefit of apoproteins binding to the chylomicron after it has left the enterocyte?
The chylomicron can bind to lipoprotein lipase which can metabolise the triglyceride component into free fatty acids and the glycerol
What are the free fatty acids and glycerol used for?
Adipocytes - storage
Skeletal muscle - generate energy
What happens to the chylomicron remanants?
They are sent back to the liver
