Cholesterol Flashcards
What three primary are fats derived from?
The diet
De novo biosynthesis - liver
Storage depots in adipose tissue
Where are bile salts generated and stored? What do they do?
Generated by liver and stored in gallbladder
During digestion they pass from the bile duct into the intestine
Emulsify fats in the intestine aiding their digestion and absorption of fats and also that of fat-soluble vitamins A, D, E and K
What does a lack of bile salts lead to?
Majority of fat passes through the gut undigested and unabsorbed
This leads to steatorrhoea
What is orlistat/tetrahydrolipstatin?
Inhibitor of gastric and pancreatic lipases
chemically synthesised derivative of lipstatin (product of streptomyces toxytricini)
Reduces fat absorption by 30% which is then excreted faecally
Name the five lipoproteins and their sources
Chylomicrons - intestines
VLDLs - liver
IDL - VLDL
LDL - IDL
HDL - liver
Role of chylomicron?
Dietary fat transport
Role of VLDL?
Endogenous fat transport
Role of IDLs and LDLs?
IDLs - intermediate LDL precursor
LDL- cholesteron transport
Role of HDLs?
Reverse cholesterol transport
What do chylomicrons acquire from HDLs when released into the blood stream?
Apoproteins
Where do chylomicrons travel from and to, to get to the bloodstream?
From the lacteals of intestine to the thoracic duct and left subclavian vein where they enter the blood stream
Where is lipoprotein lipase found and what does it bind to?
Located on the capillary endothelial cells lining adipose tissue heart and skeletal muscle
Bind to apoproteins cleaving the chylomicron
What are the properties of the shell and core of a chylomicron?
Hydrophillic outer shell
Hydrophobic core
What is cholesterol and what does it do?
Cholesterol is a steroid
It increases or decreases membrane stiffness, depending on temperature and nature of membrane
Where is most of the cholesterol in our body found?
More than 90% in cell membranes
What is dietary uptake of cholesterol?
How are physiological requirements for cholesterol met?
0.5g/day
Supplied by the liver by de novo synthesis of cholesterol from acetyl-CoA
What are the three main parts of the cholesterol synthesis pathway and where do they occur?
- synthesis of isopentenyl pyrophosphate, activated isoprene unit - key building block (cytoplasm)
- Condensation of six molecules of isopentenyl pyrophosphate to form squalene (cytoplasm)
- cyclisation and demethylation of squalene by monooxygenase to give cholesterol (ER)
What are four steps of isopentenyl pyrophosphate synthesis?
- Condensation of 2 Acetyl-CoA molecules to form acetoacetyl CoA using β=ketothiolase
- further condensation by acetyl-CoA via HMG-CoA synthase to form HMG-CoA
- HMG-CoA reduced to form mevalonate via HMG-`CoA reductase
- Mevalonate sequentially phosphorylated at hydroxyl groups positions, then decarboxylated to form 3-isopentenyl pyrophosphate
enzymes: mevalonate kinase, phosphomevalonate kinase, kinase, phospho mevalonate decarboxylase
What is HMG-CoA reductase under negative feedback control by?
End product cholesterol, bile salts and the mevalonate intermediate
What does the isoprene unit do?
Confers lipophilicty to biomolecules - gives them affinity for lipid bilayers
What two steps produce squalene from the isoprene unit?
- Dimethylallyl pyrophosphate can be produced from isopentyl pyrophosphate via isopentenyl isomerase
This then condenses with a unit of isopentenyl-pp to form Geranyl pyrophosphate (C10 compound)
Third isopentenyl-PP molecule is added to form fernesyl pyrophosphate (C15 intermediate)
- Two farnesyl pyrophospate molcules condense via squalene synthase to form C30 squalene and two molecules of pyrophosphate
What are the three steps in which squalene is cyclised to cholesterol?
1, squalene is reduced in the presence of O2 and NADPH to form squalene epoxide via squalene epoxidase
- enzyme squalene epoxide lanosterol-cyclase catalyses formation of lanosterol - formation of four rings occurs
What are the three steps in which squalene is cyclised to cholesterol?
1, squalene is reduced in the presence of O2 and NADPH to form squalene epoxide via squalene epoxidase
- enzyme squalene epoxide lanosterol-cyclase catalyses formation of lanosterol - formation of four rings occurs
- Lanosterol is subsequently reduced and demethylated to generate cholesterol
How is pregnenolone generated from cholesterol?
By the action of the enzyme desmolase
