Blomquist

Question 1

What is the usual function of cholesterol?

Answer 1

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

Question 2

Which hormones is cholesterol a precursor for?

Answer 2

progesterone, estrogen, testosterone, cortisol, aldosterone

Question 3

T/F Gall stones can be almost all cholesterol.

Answer 3

True.

Question 4

Which drug helps in the treatment of cholesterol?

Answer 4

statins

Question 5

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

Answer 5

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

Question 6

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?

Answer 6

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

Question 7

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

Answer 7

27 carbons
4 rings
OH @ Carbon 3

Question 8

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

Answer 8

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

Question 9

Is cholesterol hydrophobic?

Answer 9

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

Question 10

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

Answer 10

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

Question 11

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

Answer 11

about 2X that of glucose

around 200…ideally less

Question 12

What form does most cholesterol take in the blood?

Answer 12

that of a cholesterol ester

Question 13

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

Answer 13

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

Question 14

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

Answer 14

Cholesterol + Lecithin

Enzyme: LCAT: lecithin cholesterol acyl transferase

Question 15

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

Answer 15

Fatty Acids–LIPIDS

Pyruvate–CARBS

Question 16

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

Answer 16

NADPH

Question 17

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?

Answer 17

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.

Question 18

What are the basic steps from acetyl CoA to cholesterol?

Answer 18

Acetyl CoA
Mevalonate
Isoprene
Squalene
Cholesterol

Question 19

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

Answer 19

Acetyl CoA–>Mevalonate

Enzyme: HMG-CoA Reductase

Question 20

How do you make HMG-CoA?

Answer 20

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

Question 21

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

Answer 21

It goes on to make cholesterol.

Question 22

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

Answer 22

it goes on to make ketone bodies.

Question 23

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

Answer 23

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

Question 24

Where is the HMG CoA reductase found?

Answer 24

It is an ER bound enzyme.

Question 25

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

Answer 25

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

Question 26

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

Answer 26

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.

Question 27

Which form of HMG CoA Reductase is active.

The phosphorylated form or the dephosphorylated form?

Answer 27

the dephosphorylated form is active

Question 28

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

Answer 28

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

Question 29

How do statins work?

Answer 29

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

Question 30

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?

Answer 30

prenylated proteins
heme a
dolichol
ubiquinone
vitamin D
steroids
bile salts

Question 31

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?

Answer 31

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

Question 32

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

Answer 32

the conversion of cholesterol into bile salts

Question 33

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

Answer 33

conversion to bile acids!

Liver!!

Question 34

Describe the conversion of cholesterol to bile acid.

Answer 34

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

Question 35

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

Answer 35

Bile Acid conjugates with glycine–>glycocholic acid

Bile acid conjugates with taurine–>taurocholic acid

Question 36

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

Answer 36

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

Question 37

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

Answer 37

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.

Question 38

How is cholestryamine used to treat high cholesterol?

Answer 38

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