Cholesterol synthesis Flashcards
Cholesterol is a precursor to?
Bile salts (for far emulsification) Steroid hormones
What is Cholesterol an essential component of?
Cell membranes
Where is cholesterol located on the cell membrane?
between membrane fatty acid chains
What tendency does cholesterol have in the membrane?
to cluster
Where is the highest concentration of cholesterol and what’s the %?
plasma membrane (25% of total lipid content)
Where is cholesterol least likely to be found?
inner mitochondrial matrix (virtually absent)
How does cholesterol reduce fluidity?
by forming loose cross-links
When does cholesterol increase rigidity?
when next to saturated LCFA
What percentage of cholesterol circulates as free form?
30%
What are most esterified LCFA’s attached to?
hydroxyl group
When fat and cholesterol combine what do they form?
A cholesterol ester is formed
What form of cholesterol is more hydrophobic?
Esterified cholesterol
Where is esterified cholesterol not found?
in membranes
What transports esterified cholesterol?
lipoproteins
Where is esterified cholesterol solubilized?
in Bile (by bile salts and phospholipids)
What is an ester?
Any organic molecule produced by combining an acid with an alcohol
Can most human cells make cholesterol?
yes
Where is the primary site of cholesterol synthesis?
Liver
What extrahepatic sites for cholesterol synthesis are there?
Adrenal cortex
Intestine
Reproductive tissue (ovaries, testes, placenta)
(AIR)
What is the location in the cell for cholesterol synthesis?
cytosol
Where are all of the reactions of cholesterol synthesis at?
cytosol
Where are some of the enzymes for cholesterol synthesis attached to?
endoplasmic reticulum
Where are the carbon atoms (Acetyl Coa) coming from for cholesterol synthesis?
Oxidation of LCFA’s (OHOT)
Oxidation of pyruvate (Glycolysis)
Oxidation of ketogenic amino acids
Where does the reducing power for cholesterol synthesis come from?
NADPH (Pentose Phosphate pathway)
Where is the energy for cholesterol synthesis coming from?
ATP breakdown
Thioester cleavage
What does one mole of cholesterol require?
18 moles of Acetyl CoA
16 moles of NADPH
36 moles of ATP
What is the rate-limiting, key regulatory step of cholesterol synthesis?
HMG CoA reductase
What does HMG CoA reductase create?
mevalonate
What is the first unique compound in cholesterol synthesis?
Mevalonate
Is HMG CoA reductase reversible or irreversible?
irreversible
When is HMG CoA active?
when non-phosphorylated
When is HMG CoA inactive?
when phosphorylated
What is HMG CoA?
a membrane protein of the ER that projects into the cytosol to create mevalonate
What is the pathway to cholesterol from Acetyl CoA?
Acetyl CoA Acetoacetyl CoA HMG CoA Mevalonate Squalene Cholesterol
Where are primary bile acids made?
liver
Where are primary bile acids excreted to?
duodenum
Where are secondary bile acids made?
intestine
How are secondary bile acids made in the intestine?
Bacterial enzymes act on the primary bile salts (acids)
Why is it important for Bile salts/acids to be polar and non-polar?
Emulsification in intestine
What is the only primary mechanism for cholesterol excretion?
cholesterol excretion by bile salts
What kind of nucleus do bile acids have?
saturated steroid nucleus
What kind of position do all hydroxyl groups have on bile acids?
alpha configuration
What can bile salts/acids do at physiological pH?
they ionize and occur as sodium or potassium salts
What are the primary bile salts?
glycocholic acid
glycochenodeoxycholic acid
taurocholic acid
taurochenodeoxycholic acid
What are the secondarybile salts?
deoxycholic acid
lithocholic acid
What is the precursor to all steroid hormones?
Pregnenolone
Please recite the Cholesterol Synthesis Story.
Eat cholesterol
Muscle and liver are full of energy and glycogen
Glucokinase pushes glycolysis forward (liver)
Prep step runs
Start the Krebs cycle
Citrate is kicked out (high energy charge)
Citrate Lyase gives back the acetyl CoA
make fat and cholesterol
For sterol dependent HMG CoA reductase what does Low sterol levels in cells do?
stimulates HMG CoA Reductase (increased cholesterol synthesis)
For sterol dependent HMG CoA reductase what does high sterol levels in cells do?
down regulates cholesterol synthesis
For sterol accelerated HMG CoA reductase what does high sterol levels in cells do?
start to degrade HMG CoA reductase
What inhibits sterol independent HMG CoA reductase?
Phosphorylation from AMP-activated protein kinase
What hormones upregulate HMG CoA reductase?
Insulin and thyroxine
what hormones downregulate HMG CoA reductase?
Glucagon and glucocorticoids
What are the competitive inhibitors of HMG CoA reductase?
Statins
Can the ring structure of cholesterol be metabolized in humans?
no
How is cholesterol excreted?
Turned into bile salts and excreted in feces
Some modified by bacteria in the colon for excretion
What are the ingredients for cholesterol?
Acetyl Coa, NADPH, and ATP
Same as the ingredients for building a fatty acid
What is the main enzyme in cholesterol synthesis?
HMG CoA reductase
All biles salts end in what?
“cholic acid” or “cholate”
Is there degradation of cholesterol?
No
What is cholesterol synthesis stimulated by?
ATP
NADPH
Insulin
Fructose
What is cholesterol synthesis inhibited by?
ADP
AMP
NADP
Glucagon
What is the pathway from Mevalonate to Steroid hormones?
1.Mevalonate
2. Squalene
3. Cholesterol
4. Steroid hormones
(steps 1-3 are the same for Bile salts)
What is the pathway from Melavonate to Bile salts?
1.Mevalonate
2. Squalene
3. Cholesterol
4. Bile salts
(from mevalonate to cholesterol, the pathway is the same for steroid hormones)
