BR Biology Section VIII Passage 3

[UMICHPremed]

The passage states that "acyl-CoA-chlesterol acyl transferase (ACAT) is active in synthesis of cholesteryl ester from cholesterol and a fatty acid from coenzyme A"

Question 13 ask if people with a defect of FH, meaning they have ineffective or missing LDL receptors, would affect the metabolism of cholesterol receptors.

I. Increased intracellular cholesterol synthesis (Yes, because without LDL receptors they can't endocytosize extracellular cholesterol found in LDLs)

II. Increased LDL cholesterol in the blood (Yes, again due to lack of cellular uptake of LDL)

III. Increased activity of ACAT

The answer key says all three are true. I have a problem with #3 being true. While it is common for enzymes to catalyze the forward and backward reaction; the passage only states that ACAT catalyze the conversion of cholesterol to cholesterol esters and does not say that ACAT also catalyzes the reverse reaction. Thus, it is not reasonable to assume that it would catalyze the reverse reaction and that its activity would increase in order to raise cellular cholesterol concentration right? Furthermore, a little before, the passage states that "cholesterol synthesized in the liver is exported in the form of a bile salt or a cholesteryl ester" Thus, its possible to reason that most of cholesteryl ester is exported and there really isn't a high volume of cholesteryl ester stored in the body for ACAT to act on for the reverse reaction. Thus, III shouldn't be true? Also on the MCAT do you guys all assume that if you run into an enzyme you don't know that it also catalyzes the reverse reaction? (I mean its not always true...)

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[DrYoda]

The passage states that "acyl-CoA-chlesterol acyl transferase (ACAT) is active in synthesis of cholesteryl ester from cholesterol and a fatty acid from coenzyme A"

Question 13 ask if people with a defect of FH, meaning they have ineffective or missing LDL receptors, would affect the metabolism of cholesterol receptors.

I. Increased intracellular cholesterol synthesis (Yes, because without LDL receptors they can't endocytosize extracellular cholesterol found in LDLs)

II. Increased LDL cholesterol in the blood (Yes, again due to lack of cellular uptake of LDL)

III. Decreased activity of ACAT

The answer key says all three are true. I have a problem with #3 being true. While it is common for enzymes to catalyze the forward and backward reaction; the passage only states that ACAT catalyze the conversion of cholesterol to cholesterol esters and does not say that ACAT also catalyzes the reverse reaction. Thus, it is not reasonable to assume that it would catalyze the reverse reaction and that its activity would increase in order to raise cellular cholesterol concentration right? Furthermore, a little before, the passage states that "cholesterol synthesized in the liver is exported in the form of a bile salt or a cholesteryl ester" Thus, its possible to reason that most of cholesteryl ester is exported and there really isn't a high volume of cholesteryl ester stored in the body for ACAT to act on for the reverse reaction. Thus, III shouldn't be true? Also on the MCAT do you guys all assume that if you run into an enzyme you don't know that it also catalyzes the reverse reaction? (I mean its not always true...)

It is reasonable to assume that it catalyzes the reverse reaction. Enzymes don't affect the equilibrium constant of a reaction.

 

[UMICHPremed]

Yea, I know they do not affect the equilibrium constant, only affect rate.

For this question, if then again if cholesterol is exported as cholesteryl ester then there will not be a lot of cholesteryl ester around for ACAT to be very active so either way its activity shouldn't be high right?

 

[DrYoda]

Yea, I know they do not affect the equilibrium constant, only affect rate.

For this question, if then again if cholesterol is exported as cholesteryl ester then there will not be a lot of cholesteryl ester around for ACAT to be very active so either way its activity shouldn't be high right?

correct. There should be negligible reverse reaction due to the product being exported (common in biological systems). And the forward reaction will be decreased due to the reduced availability of substrates.

 

[addo]

Decreased ACAT activity makes sense, because the cell not being able to take up cholesterol, because of the missing or defective LDL receptors, will NOT need to convert the cholesterol it is synthesizing itself into cholesteryl esters. The end product the cell needs is cholesterol, not cholesteryl esters.

 

[UMICHPremed]

Hey sorry I made a typo in the original thread.

BR solutions says III. Increased ACAT activity is correct.

And that was my original concern.

Anyways we all seem to agree that it decreases..

 

[ilovemcat]

Um, what particular "chapter" or "subject" was this topic reviewed in. I don't recall reading about this.

 

[UMICHPremed]

Biology Part II Book Section VIII Metabolic Pathway

 

[addo]

This has led me to rethink my answer. They are rarely wrong, since these tests have been taken 1000s of times.
After looking through my biochemistry text, it says that after cholesterol is taken up, it is converted to cholesteryl esters through the action of ACAT, or it proceeds to the ER, where it downregulates HMG-CoA reductase, which catalyzes the rate determining step of cholesterol synthesis, and decreases LDL receptor synthesis. Downregulating HMG-CoA reductase would be bad until cholesterol synthesis meets the cells needs. Maybe, and I am just speculating, ACAT activity is increased to keep cholesterol from accumulating and decreasing the activity of HMG coA reductase, through negative feedback, but then again you would eventually want cholesterol synthesis to stop....so I dont know anymore.

 

[Phantastic]

Normally with these types of questions, an in-depth knowledge of the function of the enzyme will only serve to confuse you. Instead, focus on what underlying biological concept was inferred from the passage in relation to this enzyme. I do not have access to Baron, or I'd help out.

That being said, here's my stab at it based on your qualms with Baron's explanation:

Furthermore, a little before, the passage states that "cholesterol synthesized in the liver is exported in the form of a bile salt or a cholesteryl ester"

THIS is your inference statement! This will separate you from 90% of test takers. KNOWING that this statement is applicable to statement III is paramount, and certainly half the battle. Based on this statement, we have cholesterol being synthesized in the liver that we NEED to get at as a cell, so, we INCREASE ACAT activity in order to convert the ester form of cholesterol (which I assume can enter the cell, since they didn't give me a reason to think otherwise) to the normal form of cholesterol.

You could view this need by the cell as a by-product of free energy (chemistry perspective, reverse reaction, catalyst concepts, etc.), and that's the basis of their explanation.

Personally, I'm in the mind of the test writer at all times. Statement III and statements like it will usually have some sort of inference statement associated within the passage, and you can bet your life that when MCAT introduces an enzyme, they will do their very best to convolute the fundamental science behind its action.

 

[BerkReviewTeach]

Good exchange if ideas here. It's a good example of where chemistry principles govern a biological pathway.

I do not have access to Baron, or I'd help out.

That being said, here's my stab at it based on your qualms with Baron's explanation:

BR is not Barrons.

 

[addo]

Based on this statement, we have cholesterol being synthesized in the liver that we NEED to get at as a cell, so, we INCREASE ACAT activity in order to convert the ester form of cholesterol (which I assume can enter the cell, since they didn't give me a reason to think otherwise) to the normal form of cholesterol.

If you assume cholesterol can enter the cell, then the question becomes easy. But it would be just as reasonable to assume that it does not, since it says the LDL receptors are missing or defective.

 

[Phantastic]

If you assume cholesterol can enter the cell, then the question becomes easy. But it would be just as reasonable to assume that it does not, since it says the LDL receptors are missing or defective.

No, no. I said assume that the ester form of cholesterol can enter the cell. My main assumption was that the tidbit about the synthesis in the liver was applicable to statement III.

LDL receptors and their relationship with the uptake of cholesterol into the cell are the only memorized facts you need coming into this question, in my opinion.

 

[DrYoda]

No, no. I said assume that the ester form of cholesterol can enter the cell. My main assumption was that the tidbit about the synthesis in the liver was applicable to statement III.

LDL receptors and their relationship with the uptake of cholesterol into the cell are the only memorized facts you need coming into this question, in my opinion.

The ester form of cholesterol enters most cells via LDL. The liver can get them from other sources like chylomicrons, HDL, VLDL ect.


For why ACAT activity is up, I'm still stumped. Increased ACAT activity should be the result of increased intracellular cholesterol, but I can't come up with a good mechanism for why intracellular levels would be elevated.

 

[Phantastic]

Thus, its possible to reason that most of cholesteryl ester is exported and there really isn't a high volume of cholesteryl ester stored in the body for ACAT to act on for the reverse reaction.

I believe a good portion of that which is excreted is reabsorbed. Just don't know where it goes after that...mainly, how it gets into the cell....

 

[techfan]

I'm having trouble with this question also. Though in my version it says decreased activity of ACT is incorrect (semantics). The explanation says that ACAT activity increases to hydrolyze stored cholesteryl esters into free cholesterol.

Are we supposed to assume since "High intracellular levels of cholesterol stimulate ACAT, promoting esterification of cholesterol for storage." That the reverse reaction (taking cholesteryl esters from storage) is stimulated? If so, when would the enzyme ever have a decreased activity?