Blomquist Flashcards by michelle granstrom

What is the usual function of cholesterol?

used in the membrane
precursor to bile salts & acids
precursor to hormones
precursor to vitamin D

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Which hormones is cholesterol a precursor for?

progesterone, estrogen, testosterone, cortisol, aldosterone

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T/F Gall stones can be almost all cholesterol.

True.

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Which drug helps in the treatment of cholesterol?

statins

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Where is most of the cholesterol found in the human body? What effect does it have there?

in membranes!
The OH group interacts w/ surface (hydrophilic)
the body of the cholesterol is planar & rigid & is in the hydrophobic portion of the membrane
**it makes the membrane less fluid & more rigid

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What is an example of a membrane that has a lot of cholesterol? What is an example of a membrane that doesn’t have very much cholesterol?

Lots of Cholesterol: myelin sheath membrane (used for protection–>want rigidity)
Not much cholesterol: inner mitochondrial membrane

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How many rings does cholesterol have? How many carbons? Where is its OH group situated?

27 carbons
4 rings
OH @ Carbon 3

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Aside from 4 rings & 1 OH group…what are other features of the cholesterol molecule?

a few methyl groups
an 8 carbon side chain
a double bond

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Is cholesterol hydrophobic?

YES
It is also planar…
b/c of its hydrophobicity lipoproteins must carry it in blood.

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What’s the relationship b/w cholesterol & bile acids?

There is a LOT of cholesterol in bile acids. So much so that sometimes it precipitates out as gallstones.

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Compared to glucose in the blood…what are the ideal levels of cholesterol in the blood?

about 2X that of glucose

around 200…ideally less

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What form does most cholesterol take in the blood?

that of a cholesterol ester

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There are 2 ways to make a cholesterol ester. What is the way including ACAT?

Cholesterol + Fatty Acyl-CoA
Enzyme: ACAT: acyl CoA cholesterol acyl transferase
= Cholesterol Ester

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There are 2 ways to make a cholesterol ester. What is the way including LCAT?

Cholesterol + Lecithin

Enzyme: LCAT: lecithin cholesterol acyl transferase

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So…we know that cholesterol can be made from acetyl CoA. What are our 2 major sources of Acetyl CoA?

Fatty Acids–LIPIDS

Pyruvate–CARBS

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What do you need a lot of to form either cholesterol or fatty acids?

NADPH

So…we have a ton of acetyl coA trapped in the mitochondrial matrix & we need it in the cytoplasm for cholesterol biosynthesis. How do we move it?

Acetyl CoA + OAA–>Citrate via citrate synthase.
this goes thru SLC25A1 on the inner mitochondrial membrane. It diffuses thru the outer mitochondrial membrane.
ATP-citrate lyase breaks citrate into OAA & Acetyl CoA.
Now, the acetyl CoA is in the cytoplasm & ready to go. For more details look @ the figure.

What are the basic steps from acetyl CoA to cholesterol?

Acetyl CoA
Mevalonate
Isoprene
Squalene
Cholesterol

What is the key regulatory step in cholesterol synthesis? What enzyme is involved?

Acetyl CoA–>Mevalonate

Enzyme: HMG-CoA Reductase

How do you make HMG-CoA?

2 Acetyl CoA–>Acetoacetyl CoA
Acetoacetyl CoA + H2O –>HMG CoA
This last step uses the enzyme: HMG CoA Synthase

If the HMG CoA is made in the cytosol…what is the result?

It goes on to make cholesterol.

If the HMG CoA is made in the mitochondrial matrix…what is the result?

it goes on to make ketone bodies.

Once again, what is the key regulated step in cholesterol synthesis?

HMG CoA + 2 NADPH –>Mevalonate
Enzyme: HMG CoA reductase
Note: 2 NADPH per 1 mevalonate

Where is the HMG CoA reductase found?

It is an ER bound enzyme.

What are the ways in which HMG CoA reductase is regulated? What are the 2 most important ways?

1. feedback inhibition 2. phosphorylation/dephosphorylation Most important: 3. Control of gene expression 4. Rate of enzyme degradation

Why is it that after changing diet & exercise...many people don't see a change in their cholesterol levels?

b/c of feedback inhibition the more cholesterol-->the less HMG CoA reductase is active the less cholesterol-->the more HMG CoA reductase is active If you reduce cholesterol intake, maybe the enzyme will just boost its activity. This is why statins have been so helpful.

Which form of HMG CoA Reductase is active. | The phosphorylated form or the dephosphorylated form?

the dephosphorylated form is active

Explain a little about the control of gene expression as a way of regulating HMG CoA reductase.

SREBP when not stuck in the ER membrane binds to target gene in the nucleus & increases the production of HMG CoA reductase. This happens in response to low sterol levels. SREBP: sterol receptor element binding protein

How do statins work?

One of the groups on the statins competes with HMG CoA for the active site of HMG CoA Reductase... This reduces the cholesterol that ends up being made

As a result of taking statins...you sorta shut down a long pathway that could contribute to making other things aside form cholesterol...this doesn't seems to be a problem BUT what products might you have less of as a result of taking statins?

``` prenylated proteins heme a dolichol ubiquinone vitamin D steroids bile salts ```

Okay...so this nice man doesn't want us to memorize all the details of cholesterol biosynthesis...but we should know the basics. What are the basics?

``` You go from: C5 molecule to C10 molecule to C15 molecule to C30 molecule + 21 more steps to Cholesterol (a 27 carbon molecule) **Cyt P450 used a lot ```

Aside from playing a huge role in cholesterol biosynthesis...what else is Cyt P450 important in?

the conversion of cholesterol into bile salts

What is the major metabolic fate of cholesterol? Where does this occur?

conversion to bile acids! | Liver!!

Describe the conversion of cholesterol to bile acid.

It involves cyt P450 First step: 7-hydroxylase, adds an OH group produces: 7-hydroxycholesterol **then more OHs are added to produce various bile acids. **takeaway: extra OHs make the bile acids polar on one side, apolar on the other...helps their fcn *Also: less common pathway involves 27-hydroxylase instead

What are the 2 main things that bile acids conjugate with? What does this produce?

Bile Acid conjugates with glycine-->glycocholic acid | Bile acid conjugates with taurine-->taurocholic acid

Which form of bile is more productive as an emulsifier: bile acids or bile salts? Why?

BILE SALTS are better. This is b/c they are more polar with the conjugation.

Which form predominates in the duodenum: bile acids or bile salts? Why?

Bile salts are more common in the duodenum b/c their pH is around 4. The pH of the duodenum is 3-5. The pH of bile acids is around 7.

How is cholestryamine used to treat high cholesterol?

It has a positively charged nitrogen group on it. Negatively charged bile acids bind to it. It removes them from the body. Thus, the body uses the cholesterol it has to make more bile salts. Still not as effective as statins Bad side effect: bloating, gas