CR II - Cholesterol Metabolism Flashcards
What do all of the carbon atoms of Cholesterol come from?
Acetyl-CoA
What is the control point in synthesis of mevalonate from acetyl-CoA? What enzyme is involved? What is required for this step? What is produced? What class of drug is the enzyme inhibited by?
HMGCoA reductase
Required: HMGCoA, 2 NADPH, 2H+
Produced: Mevalonate, 2 NADP+, CoASH
HMGCoA reductase inhibited by statins
Generally, where can cholesterol synthesis take place? What two sites are particularly active?
Essentially all nucleated cells can produce cholesterol
Liver and steroid producing organs very active
Where can HMG-CoA reductase be found in the cell?
Embedded in ER
What is mevalonate converted to, requiring 3 phosphorylation and 1 decarboxylation? What is special about this compound?
Isopentenyl diphosphate
Its and isoprene element - easily polymerized
How many isoprenoid units are required to form squalene? Describe the basic process from istopentenyl to squalene
6
Process: 2 isoprenoid elements form Germany like diphosphate. A 3rd isoprenoid element is added to form farnesyl diphosphate. Two of these are used to synthesize squalene
What is the first sterol produced in the cholesterol pathway? From what? What 2 things are required?
Lanesterol
From squalene
Requires NADPH and O2
What are the 5 steps to convert lanosterol to cholesterol?
Removal of 3 methyl groups
Reduction of C24 double bond
Moving of another double bond
Where does conversion of lanosterol to cholesterol take place? Why?
ER
Because it is poorly water soluble
What are three other important products of the cholesterol synthesis pathway? Why is each important?
Prenylated proteins - Some membrane-associated proteins are prenylated with farnesyl or geranyl residues, helping anchor the protein to the membrane
Dolichol - formed form farnesyl diphosphate + up to 16 isopentenyl residues. Required for synthesis of N-linked glycoproteins
Ubiquinone - required for ETC
What are 4 general fates of cholesterol in the liver?
Formation of cholesterol ester
Transported to other tissue
Secreted into bile
Used to synthesize bile acids/salts
What enzyme is used to catalyze the formation of a cholesterol ester? What are the 2 fates of the cholesterol ester?
Acyl CoA-cholesterol acyltransferase
Packaged into VLDL or stored in liver for future use
What are two uses of cholesterol when it is transported to other tissues? Which is the only one to break open the steroid ring?
Steroid hormone synthesis
Vitamin D synthesis - breaks open steroid ring
What organ is the main organ to control cholesterol metabolism for the whole-body?
Liver
What are two ways the liver received excess cholesterol from extrahepatic tissues?
Through LDL receptor and reverse cholesterol transport
Where are two places cholesterol secreted to from the liver? Via what?
Secreted into bloodstream Via VLDL
Into bile
What are the three main regulatory targets of cholesterol metabolism in the liver?
HMG-CoA reductase
LDL receptor
7alpha-hydroxylase
What does sterol-regulatory element-binding protein (SREBP) bind to? Of what gene? What does it cause?
Binds to Sterol-regulatory element
Or HMG-CoA reductase gene
Stimulates transcription of gene
How do elevated amounts of cholesterol within the liver cell control cholesterol synthesis? Describe process
Prevent SREBP from binding to SRE
SREBP interacts with SREBP cleavage-activating protein(SCAP) on ER membrane, which remains bound to this when cholesterol is also bound to SCAP.
Prevents SREBP from leaving ER
When cholesterol levels drop, SERBP:SCAP complex moves to golgi
Complex undergoes proteolysis, allowing SREBP to be released and travel to nucleus
What regulates the proteolysis of HMG-CoA reductase? How?
Cholesterol
When bound to sterol sites on HMG-CoA reductase, it is more susceptible to proteolysis
How does phosphorylation affect HMG-CoA reductase? What three factors promote phosphorylation? Which two promote dephosphorylation?
Less active when phosphorylated
Promoters of phosphorylation: glucagon, glucocorticoids, cholesterol
Promoters of dephosphorylation: insulin and TH
How is regulation of LDL receptors simulate to HMG-CoA?
What is one way LDL receptors are destroyed?
Under same regulatory control by SREBP - when this binds to gene, LDL receptors are transcribed
LDL receptors destroyed when PCSK9 is bound, promoting transfer to lysosomes after the receptor is moved into the cell
What is the commitment step in bile acid synthesis? How do increased liver bile acids repress the synthase of the enzyme at this step?
7alpha-hydroxylase
Increased bile acids bind the farnesyl X receptor (FXR) which will suppress the synthesis of 7alpha-hydroxylase
