Lecture 44: Cholesterol Synthesis and Elimination Flashcards
Where is cholesterol mainly found in the cells and what does it do there?
Cell membranes and it gives it a certain structure/ rigidity
T/F: The amount of cholesterol from the inside of the cell to the outside decreases.
False. It increases as you go from inside to outside of the cell. Organelles with membranes (i.e. nucleus/ ER, etc) have less cholesterol in them than the plasma membrane.
How many carbons are in cholesterol?
27 carbons
Which are the most commonly modified carbons in cholesterol?
C3 (OH group) and C17 (side chain)
Where is cholesterol synthesized?
liver and intestine so it is not required in the diet
What are two common reasons for high cholesterol?
Too much cholesterol in the diet
Hyperactively producing cholesterol because of genetic predisposition
How is cholesterol eliminated from the body?
Converted into bile acids/ salts in the liver
stored in gall bladder/ secreted into intestine
small percent is excreted in the feces
What is the primary form in which cholesterol is transported in the plasma?
Cholesterol ester (esterification at C3 with fatty acid)
Packaged into lipoprotein particles
How do you synthesize HMG CoA?
You use thiolase to make acetoacetyl CoA from acetyl CoA.
Then you use HMG CoA synthase on acetoacetyl CoA to make HMG CoA.
What is the rate limiting enzyme for the synthesis of cholesterol?
HMG CoA reductase
How much ATP/ NADPH is necessary to make cholesterol?
18 ATP
14 NADPH
cholesterol synthesis needs a lot of energy!
Is cholesterol synthesis localized to one portion of the cell?
No! It occurs all over the cell (i.e. peroxisomes, ER, cytosol, mitochondria)
What transcription factor regulates cholesterol synthesis genes?
SREBP (sterol responsive element binding protein)
How does cholesterol regulated gene expression work when there is high intracellular cholesterol?
There is a decrease in transcription of nearly all genes encoding proteins in the cholesterol synthesis pathway
How do you make mature proteolytically processed SREBP?
SREBP binds to SCAP (SREBP Cleavage Activating Protein)
When ER sterols are low (low cholesterol) complex moves to golgi where it is cleaved by Protease 1 and 2
Activated SREB moves to nucleus and activates expression of cholesterol synthesis genes
What happens to HMGR when there is an increased level of intracellular cholesterol?
HMGR has a decreased stability and it becomes mis-folded and degraded
T/F: Phosphorylated HMGR is active.
False. HMGR is inactivated by phosphorylation.
It is phosphorylated by AMP kinase.
What does insulin and glucagon do to HMGR expression and activity?
Insulin stimulates HMGR expression and activity.
Glucagon inhibits HMGR expression and activity
What are statins?
Statins competively inhibit HMGR. They mimic the transient intermediate mevadyl CoA.
Why is there so many different statins?
Diversity of medication is important to treat variety of different people.
What is the chemical name of Zetia?
ezetimibe
What does zetia do?
It acts as a small intestine brush border.
It has no side effects because it does not enter the blood stream and inhibits the absorption of cholesterol but not triglycerides/ fat- soluble vitamins.
What is Vytorin?
It is a combination drug of ezetimibe and simavastatin (i.e. a statin) that reduces cholesterol levels when compared to statin alone.
Why is Vytorin useful?
It permits reduced doses of statins, which have side effects.
What is the principal mechanism of eliminating cholesterol from the body?
Excretion of bile salts
Cholesterol is a precursor to _________.
bile salts and bile acids
Where are bile salts and acids synthesized, stored and secreted into?
Liver
gall bladder
intestine
What do bile acids/salts do?
they emulsify dietary lipids making them accessible to pancreatic lipases
aid in the absorption of fat soluble vitamins (ADEK)
What is the rate limiting enzyme for bile acid formation?
7- alpha- hydroxylase
What inhibits/ promotes 7 alpha hydroxylase?
- cholic acid
+ cholesterol
How do you make a bile acid?
You add OH group to the C7 of cholesterol
Primary bile acids give rise to _______ which gives rise to ________ which are bile acids conjugated to glycine or taurine in the liver.
secondary bile acids
bile salts
How do you treat hypercholesterolemia?
It is treated with compounds that sequester bile acids in the intestine.
These sequesterants:
- prevent the reabsorption of bile acids
- increase the conversion of cholesterol to bile acids
- increase bile salt elimination in feces
