#36 Biochemistry Cholesterol in the Body Lecture for Kevin Ahern’s BB 451/551
22
August

By Adem Lewis / in , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , /


Kevin Ahern: How was the exam? [class murmuring] Kevin Ahern: Ehhh. How many thought they did well? Nobody’s going to stand up in
front of their friends, right? How’d you like the format? [class murmuring] Student: Ehhhh. [class laughing] You guys are in a
pretty good mood today. Any thoughts? Feedback? What’s that? Student: I like writing it out. Kevin Ahern: You like writing it out. Student: There was some nasty matching. Kevin Ahern: Nasty matching. Okay, other thoughts? One of the reasons the
format changes is that we don’t have calculations
this term so that’s what tended to drive that other format where calculations and
more involved processes. Things this term tend to be briefer and so the exam questions
don’t cover as much material, and that’s part of the
reason for doing it. Another reason is because
there’s no recitations I don’t have TAs and so grading has, we have simplify that also. So both of those combine
to give us this format. Anybody have time as an issue? Yeah, generally not in this course. They’re not graded yet. I will be talking to the TAs soon. I don’t anticipate
they’ll be ready today. I wish they were but I
don’t think they will be. So it’ll probably be
Monday and I’ll let you know as soon as I know, as always. I want to finish up
talking about the movement of cholesterol and lipids,
other lipids, in the body today. And I’ll go back and
talk about that little bit of regulation that I didn’t talk about with cholesterol before. And then we’ll talk about
some other byproducts of cholesterol and then we’ll
start on fatty acid oxidation. So a fair amount to
get on our plate today. Last time I went through
at least the first parts of this schematic saying that
you’d just eaten a Big Mac and you’ve absorbed,
through your intestines you have absorbed some lipids. These include fats,
they include fatty acids, they include cholesterol. They include fat-soluble vitamins. Basically things that are
water-insoluble are what’s in this little mix that’s there. Those I said got packaged
up by the lymph system in the chylomicrons and
the chylomicrons went out, got broken down to remnants, and the remmants made
it back to the liver. And the liver had a
little receptor there that grabs a hold of these and says, “Okay, I’m going to
internalize them,” and it did. Now I said we have some
factors contributing to the uptake of these. And these factors
include how much capacity the liver has to hold on to lipids. How much capacity it
has to hold on to some of those lipids including cholesterol. And last, how much the body is needing. So it was about that point
where I finished last time and I said your body,
the liver has to respond to needs and it has to
basically deliver lipids, which include cholesterol, to target tissues when they need it. So the way the liver
does this is it dumps out into the bloodstream. It actually packages up a
new lipoprotein called a VLDL and that VLDL stands for
very low density lipoprotein. And I described how the VLDLs
go out, they get chewed up, and as they get chewed
up they get smaller and smaller until they get to LDLs. And I said LDLs are what the
doctors call bad cholesterol because they have, A,
the highest percentage of cholesterol present, but B,
also because it’s these guys, the LDLs, that are
linked to the formation of atherosclerotic plaques. So LDLs play a role in atherosclerosis. Atherosclerosis leads to
heart attack, leads to stroke. And they’re basically,
what we call plugging of the arteries that’s
what they’re talking about. Well I haven’t gotten to
how the liver controls things so I want to do that
and then I’ll come back and talk about the formation
of atherosclerotic plaques. The liver has put out some
VLDLs and the liver needs to know have I put out enough,
have I not put out enough? And the way the liver
does this is it measures the amount of LDLs that
come back to the liver. It measures the amount of LDLs
that come back to the liver. And unfortunately this is not
directly shown on this figure. The liver has a receptor on
it called the LDL receptor. Now, if everything’s working
great, here’s what happens. The liver puts out a bunch of VLDLs. They get used by the
body and if they get used by the body what’s going
to happen to the amount of LDLs that’s going to be left? Well it’s going to be low. So the liver looks at this
and it asks its receptors, “Hey, are the LDL concentrations
high or is it low?” If the LDL concentration
is high the liver says, “Oh, the tissue doesn’t need stuff. “I’m going to quit putting out VLDLs.” If the LDL concentration
is low the liver says, “Oh, the tissues are starving,”
and it puts out more VLDLs. So the liver uses the amount
of binding to the LDL receptor as an indicator of the
body’s need of lipids. The more that gets bound
the less it puts out. The less that gets bound or puts out. Well why do people have
high cholesterol then? Well there are a couple reasons. One is if the liver is at capacity
it can’t really absorb more. It’s going to be putting out
things as fast as it can because, “Hey, I’ve got no room
to store stuff,” right? You probably have stuff in
your parent’s house somewhere. Your old bedroom is all packed
with your stuff and you said, “Oh wow, I got this, a
whole bunch of new stuff “I bought for my apartment. “Can I put my other
stuff in the apartment,” and your parents are going to say, “Okay, but something else
is going to have to go.” That’s what happens here. So if the liver’s already at capacity that’s going to be a factor. That’s why I say when we
think about diet in terms of how much you can reduce,
that is increase your liver’s capacity but reduce these other things that are out here by your diet. And if you can’t change
that with your diet then we go to other things. So diet’s a first approach. Another factor that will
contribute to the cholesterol levels will be how well do the
LDLs bind to these receptors? Now the LDL receptors that the
liver has are very much like but not identical to LDL receptors
that are on other tissues. Remember the other tissues
are grabbing those LDLs and they’re internalizing them
and that’s how they’re getting cholesterol directly into them. That’s the only way they get cholesterol in is through those
tissue LDL receptors. The liver’s LDL receptors are different. So if there’s something that
prohibits the liver’s LDL receptor from binding with
LDLs, what’s going to happen? Well the liver will never
know what the LDL levels are. In fact the liver, if it can’t
bind to the receptor properly, is always going to be putting
out more VLDLs because it says, “Wow these tissues are just starving.” Meanwhile these VLDL levels are
floating up here pretty high. So if your LDL receptor
isn’t perfect at binding those LDLs that can be
a contributing factor. Now in extreme cases,
and I’m going to show you an extreme case in just a second, there’s a genetic disease called
familial hypercholesterolemia. I’m not going to spell that. It’s in your, I’ll put
it on the highlights. You’ll see it. But it’s a genetic
disease in which a person’s LDL receptors on the liver are gone. Totally nonfunctional. It’s extraordinarily rare. And interestingly enough in this class about seven or eight
years ago I had a student that came up to me
after class and she said, “I know about that, my kid’s got it.” And I said, “No way.” Because what happens is it’s
a very very rare disease. And children who get it typically
are dead by the age of ten. They die of heart
attack because their body is putting out so much VLDLs and
LDLs are made as a consequence that the atherosclerotic plaques form and they die of heart attacks
or stroke at a very early age. She said, “No I’m sure he has it.” I said, “okay.” So she goes and she checks and
she comes back and says, “Yep. “That’s what he’s got.” And I said, “Really?” So I asked her for
her story and she said, “Well, when he was about
six or seven years old, “he had these sores that
started appearing on him. “I took him to the doctor.” Doctor says, “Oh, he’s got
pus” or he’s got whatever. He doesn’t know what it is. And they never seem to get better, they never seem to get better. Finally they fortunately
get this kid in front of a doctor who goes, “You
know what those sores are?” and I’m going to show you these sores. Student: Aww. Kevin Ahern: It’s not
gross, it’s not gross. This is what they look like. Those were cholesterol. Well fortunately the doctor
recognized and had the kid tested to see if he had hypercholesterolemia
and in fact he did. They checked his LDL
levels in the bloodstream and where 200 would be
considered a relatively high amount that they would
put you on medication for, this kid’s level was 700. I said, “You’re kidding!” you know? Well there’s a happy ending
to this story actually, a very happy ending. They recognized it and they treated it. And the age of a person
dying of hypercholesterolemia pretty much changed
dramatically when they got the statin drugs and other drugs
that can actually physically lower cholesterol levels. So they took this kid. They put him on every
statin and every drug that they could that lowered
the cholesterol levels. And with that his cholesterol
levels are down to about 200 or so where it’s a
much more normal level and the kid’s going
to live a normal life. So that’s kind of a cool story. I couldn’t believe I
actually met somebody, knew somebody who had this
because it’s on the order of they estimate maybe two or
three people in the country, in the U.S., might
have it at a given time. So it’s a pretty rare disorder. Happy ending though. So that’s what happens if your liver LDL receptors are not functioning. The liver doesn’t know,
has no way of knowing what’s out there. So he just keeps putting
out more and more and more out there and the liver just
gets pretty tired of all of that. What else
did I want to say about that? That’s an atherosclerotic plaque. That’s probably even more gross. How does about
atherosclerotic plaque form? I said it forms from LDLs and
one of the ways in which it forms is it appears that LDLs are susceptible to reactive oxygen species,
more so than the other lipoprotein complexes are. That means they can be
much more readily oxidized when they encounter reactive oxygen. We’ve seen reactive oxygen
in mitochondria and we said, “Well we’ve got these enzymes
that deal with that,” okay? Well if the reactive oxygen
species wins the race, you’re in trouble. Inside of cells I’ve
got superoxide dismutase. Outside of cells, what do I have? Not as much. Outside of cells reactive oxygen
species are going to be bad. Guess who has high concentrations of reactive oxygen
species in their blood? Smokers. Those are extracellular. Much more likely they’re going to have oxidation of their LDLs. When oxidation of LDLs occurs
a variety of things can happen. But one of the things
that can happen is that that can damage a part of the
artery where the LDL is located. The LDL may get stuck to
the artery as a result of that. And that forms the basis by which the atherosclerotic plaque happens. Because what happens
is the immune system looks at that damaged
LDL, that damaged artery, and says, “Oh, we’ve got a problem. “Let’s go attack it.” The immune system attacks
it with macrophages that binds one LDL that binds more and what happens is they accumulate. You form what are
called foam cells because they are rich in these macrophages, they’re rich in the LDLs,
they’re loaded with cholesterol, and they start to grow
and they block the artery. So it’s for that reason that your doctor calls LDL the bad cholesterol. It actually is much
more likely you’re going to have damage happen as a
result of reactive oxygen species and you’re going to have this formation of this mass that’s going to
happen as a result of that. That’s the bad news. The good news is that
there’s also a cholesterol that your doctor calls good cholesterol, and that’s what’s actually
shown back here on the fates. And you see HDL. HDL is a little hard to
understand, and HDL is basically a scavenging form of
lipoprotein complex. It’s grabbing pieces that
haven’t been handled properly. They can actually help to
scavenge LDLs or pieces of LDLs that are there and will physically lower the problem molecules
in your bloodstream. Your doctor’s going to be happy
if your HDL levels are high. Your doctor’s going to be
happy if your HDL levels are high because that means a
lot of stuff is getting hauled back to the liver that would
otherwise cause problems for you. How do you increase your HDL levels? Exercise. Stop smoking because
smoking will lower HDLs and smoking will elevate LDLs. And diet. If we look at diets that are richer in unsaturated fatty acids,
polyunsaturated fatty acids, we tend to associate
those with higher levels of HDL and lower levels of LDL. If it goes saturated it
tends to reverse that. Question? Student: Yeah, are they effective at
taking apart the plaques once formed or do they just
filter out the solution? Kevin Ahern: Yeah. Are HDLs effective at taking
apart the plaques once they form? To my knowledge no, but
I have actually heard of certain diets that
may be linked to that. So I can’t say an absolute
no to that question. So HDLs are what you
really want to get going. Probably the best way to get
your HDLs high is exercise. Exercise, exercise, exercise. If you want a good
prescription for health, that’s the place to start. So those are the
considerations for the movement of cholesterol in the body. I want to come back and talk
about this regulatory pathway and there’s a little
bit of complexity to that that I’m going to show you. When we think about
the regulation of levels of synthesis of cholesterol in our body, remember we’re talking
about synthesis now. Not movement, but synthesis. And by the way, I
think I said before but if I didn’t I’ll say it again here. There are three considerations
for cholesterol in your body. Three considerations. Number one, you have
to think about how much your body is making. Second, you think about how
much you’re getting in your diet. And third, you’re thinking
about how much you’ve got stored. Those three are very
important to think about. Dietary cholesterol can be controlled by your diet, obviously. Synthesis of cholesterol
can be controlled to some extent the statins. Statins, whatever you want to call them. S-T-A-T-I-N-S. The body has a complex regulatory system for the controlling the
synthesis of cholesterol. I told you part of that. I talked about HMG-CoA reductase and how that HMG-CoA reductase
was a regulatory enzyme in root to synthesis of cholesterol. I said it was feedback
inhibited meaning the enzyme was turned off as the concentration of cholesterol accumulated. But there are other things that help control cholesterol synthesis. So what I’m getting ready
to show you right now is controlling how HMG-CoA
reductase is even made. That’s what this figure
here is showing us. How do we control
whether or not it’s made, because remember that’s one of the ways we can control an enzyme. Whether or not it’s made. Well to understand this
we have to understand a couple steps of membrane proteins. There’s a couple sets
of membrane proteins. One’s called SCAP. And the other’s called SREBP, sterol response element binding protein. You’ll probably call it SREBP. Now SREBP appears in three different forms on this figure. And this is where students get confused. I’m going to call this SREBP A. I’m going to call
this form here SREBP B. And I’m going to call this form SREBP C. You’ll see why I did that in a second. This figure isn’t completely
clear in my opinion. When we have levels of cholesterol
in our body that are low, we see what happens in this picture. When cholesterol levels in
the body are low the body says, “I need to synthesize some cholesterol.” What happens? Well we’re looking at the membrane of the endoplasmic reticulum right here. And the membrane of the
endoplasmic reticulum, we have the SCAP which
has a portion of itself that binds to the SREBP A. SREBP A is the one
that’s completely intact. As long as the cholesterol
levels aren’t low we have this staying at the top. When cholesterol levels start to fall what we see is there’s a
serine protease that comes in and it basically cuts
SREBP into two pieces. That generates, I’m sorry,
SREBP A into two pieces. One of these pieces is over here. It’s called SREBP B. And we see that it’s no longer
tied to this SCAP protein. Notice this is also-actually
I should also point out, I didn’t say this, when
cholesterol levels fall this whole complex is
transferred to the Golgi. It’s in the Golgi where
this serine protease resides. So when cholesterol
levels fall this complex of this membrane gets
transferred to the membrane of the Golgi and now the
serine protease comes along and does a number on
SREBP A, creating SREBP B. SREBP B is free to move in the membrane. It’s no longer tied to this SCAP. It’s no longer tied to the
SCAP so it can go over here and interact with another protein, an enzyme in the membrane
called a metalloprotease. You saw an example of that last term. And metalloprotease will clip off SREBP C. So now we’ve got this little
piece that’s free to go. This is the place where the
figure gets a little inaccurate. SREBP C is a transcription
factor meaning it’s a protein that binds to a specific
promoter sequence in the DNA. I’ll repeat that. SREBP C is a transcription factor. When it’s released it can go to
the DNA and bind to a specific promoter in the nucleus, in the DNA. That promoter, and that’s
what’s confusing here, the promoter is called SRE. Sterol response element. So SREBP C is the blue guy. It is bound to a portion
of the DNA called the SRE. And when SREBP C binds to
the SRE transcription occurs and guess where SRE occurs? It’s the promoter
for HMG-CoA reductase. So what we see is when
cholesterol levels are falling we’re releasing a transcription factor that goes to the nucleus. It turns on the transcription
of HMG-CoA reductase and that’s a critical enzyme
for making cholesterol. I’ll slow down, let you write that down, and also take any questions. Jodie? Student: Do those portions reassemble or are they resynthesized? Kevin Ahern: These portions
do not reassemble, no. Does everybody got that? There’s a lot of stuff there
and it’s not the best figure. That’s why I call it A, B, and C because I think that helps you
remember what’s there. So SREBP C is bound to the
sterol response element. That’s a sequence in the DNA that’s ahead of the HMG-CoA reductase gene. It goes and turns on that gene. Bang, you can start making cholesterol. Yes sir? Student: [inaudible] Kevin Ahern: And cholesterol
in turn will feedback the HMG-CoA reductase
and I’m going to show you one other thing it does
in a second as well. So that’s a lot of material there. Let’s take another look at
how this guy controls things. So we’re back looking at SCAP again. There’s our SREBP A. This is depicting what’s happening when we have a lot of cholesterol. When we have a lot of cholesterol, this guy is interacting
with a protein called Insig. There are different
Insig’s that are out there. This is one of them. Insig, if there’s a lot of cholesterol, will prevent the movement to the Golgi. Insig will prevent the
movement to the Golgi. So that process you saw in
the last slide will not happen if cholesterol levels are high. If cholesterol levels
fall this detachment occurs because Insig only
interacts when cholesterol is found in here. If cholesterol levels
fall this gets detached and this guy goes over to the Golgi and what you saw in
the last slide happens. So this is a way of
using cholesterol levels to control what happens to SREBP A. Now there’s one last thing
that cholesterol can stimulate and that’s actually the
degradation of HMG-CoA reductase. So now we’ve seen-this
tells us there are several very important things about this enzyme. We control how it’s synthesized. We control how this guy’s
allosterically regulated. Cholesterol can turn it off. We control how much of it
it is by breaking it down, and I’m going to show
you that in this slide. And last, we control this
enzyme by covalent modification. Phosphoralation turns
off HMG-CoA reductase. It can be phosphorylated and when that happens it’s turned off. So four ways of controlling that enzyme. I’m going to repeat them
because I know you probably didn’t get them the first way around. We control synthesis. We control allosterically. We control its rate of degradation. And we control it by
covalent modification. Four different ways. That tells us this enzyme is very, very, very important to our body. So let me take you through this slide and then we’ll be done with this. Here is the membrane of a cell that has in it HMG-CoA reductase. It’s a membrane protein. In the membrane of this
cell there are another group of Insigs, you see it right here, another group of Insigs
that is associated with what are called ubiquitinating enzymes. Ubiquitinating enzymes. What are ubiquitinating enzymes? Ubiquitinating enzymes play roles in controlling degradation of proteins. Now I want to make a clarification
here because somebody asked me something earlier in the week that they were a little confused as well. There’s a difference between
ubiquitination and ubiquinone. Ubiquinone is a molecule. Ubiquitin, which is what’s
happening here, is a protein. It’s a small peptide. Coenzyme Q is also called ubiquinone. It’s also called
ubiquinone, so don’t confuse that with what’s happening here. There’s nothing related to that. Now, what’s happening? When cholesterol levels are
high, these guys associate. You see sterols. That means there are plenty
of things like cholesterol, like lanosterol, like various
things that end in “-ol.” When these are high,
this association between Insig and HMG-CoA reductase occurs. That brings these guys in
place and it starts putting on this small peptide
onto HMG-CoA reductase. What that is is a
target for degradation. It’s actually like a flag
the cell uses that says, “Destroy me.” This destruction tag is used by many different enzymes in the body. The body has proteins
that have a lifetime and that lifetime is
governed partly by how long it is before they get degraded. And the signal for
degradation is ubiquitin. So once this guy gets
this on here we see that HMG-CoA reductase gets
destroyed and we’re gone. So what that means is as
cholesterol levels are high, again, we’re going to see
destruction of the enzyme. Questions about that? Yeah, Lacey? Student: [inaudible] Kevin Ahern: I’m not
quite sure I heard you but I think you said does this contribute to cholesterol levels in the blood? Student: Yeah, [inaudible.] Kevin Ahern: That’s a good question. Basically anything that
is affecting the synthesis of cholesterol, and
this definitely affects the synthesis of cholesterol, will have a role in
cholesterol levels in the blood. So when we take a drug like
a statin we’re inhibiting this enzyme allosterically,
one of the four ways in which we can control this enzyme. This, because of this
ubiquitination system, does indeed play a role
in controlling how much of the enzyme is available for control. Jodie. Student: Are there any
other non-statin drug classes that are used primarily
or at least quite often to control it by one
of the other methods? Kevin Ahern: So his question
is are there other drugs that are used to control
by different methods and he’s unfortunately
opening a can of worms. So I’ll answer his
question and not hold you responsible for it. How’s that? That’s where you go, “Oh, I
love the knowledge,” right? Yeah, there are other
things, other strategies for lowering cholesterol
that involve other drugs and one of them is
what’s known as recycling. So our body, in addition
to make cholesterol, the only way we get
rid of cholesterol is by excreting it in our feces,
and our intestines have further down in them an
ability to reabsorb cholesterol, to do recycling. So one of the strategies
for lowering cholesterol is to increase fecal excretion, and to do that you inhibit the
reabsorption by the intestine. That doesn’t have anything
to do with these four methods but it’s a fifth method that is involved in controlling cholesterol levels. And that one turns out
to be very effective and it’s used in one of those rare cases where statins either
don’t work or where people have reactions as a result of statins. The kid I told you about
was taking both inhibitors of reabsorption and the HMG-CoA
reductase statins as well. So yes there are other things
that can be done in that. I don’t know of anything that
specifically targets this, no. Yes? Student: [inaudible] Kevin Ahern: Well liver
cells can play a big role in this cholesterol metabolism. So this, liver cells
would be a good example but that’s not the only place
where cholesterol’s made, yeah. That is a complex story. Cholesterol as I told you
is a complicated molecule and it is a molecule that is
still being actively studied. I think I’ve mentioned
in this class before that there are five Nobel
Prizes that have been won for cholesterol and people still haven’t gotten cholesterol all figured out. So a lot of things going on there. The last thing I want
to say about cholesterol are the metabolites of cholesterol. So cholesterol is not an endpoint. We use cholesterol in our
membranes but that’s not the only thing we do with
cholesterol in our bodies. I referred earlier to the
synthesis of bile salts. I didn’t show you what they are but I will show you what they are now. Bile salts you may
recall are these detergent like molecules that are
present in our stomach that help us to emulsify
fat as we eat it. I said it was important that we convert that fat into something
that was soluble in water, and the way to do that
was with detergent. These are the detergents. Glycocholate, taurocholate. There are other examples. This is just two of them. And these molecules are
made from cholesterol. Cholesterol is not very
water-soluble at all but when it gets these groups put on, there’s a hydroxyl group there, some additional OH’s on there. There’s a sulfate over here, excuse me, and some additional OH’s over here. These molecules are in
fact much more water-soluble than cholesterol is and
so they actually help in that emulsification process. So bile acids or bile salts, you can call them either one
for as far as I’m concerned, are made from cholesterol. They play very important
roles in the digestion process. Another thing that
cholesterol is used for is to make steroid hormones. There are several classes
of steroid hormones and you will see in
this category here that cholesterol is a precursor
to something called pregnenolone, and
pregnenolone gives rise to the major classes of steroid
hormones, the glucocorticoids, mineralocorticoids, androgens
the male sex hormones, and estrogens the female sex hormones. I think I’ve got a figure showing here. I want to focus on one component of that steroid hormone
synthesis and that is the synthesis of female sex
hormones and male sex hormones. So the male sex hormones are
the androgens as a category, and here’s testosterone. Another related one,
androstenedione, here. If we look at what’s
happening in going from either testosterone to estradiol or
androstenedione to estrone, we see in each case a
benzene ring is being formed. This is a very unusual reaction. A very unusual reaction. In all of biology
there are only a handful of places where benzene
rings are made in a ring where there wasn’t one before. Very, very rare reaction. The enzyme that catalyzes this
formation of the benzene ring is called an aromatase,
A-R-O-M-A-T-A-S-E. Female sex hormones, the
production of female sex hormones, requires action of this
enzyme known as aromatase. Now it turns out that there are tumors that are responsive
to female sex hormones. And yes, guys, you
have some of this too. There are tumors that
are responsive to these. For example, and many of
these are breast cancer tumors though there are other tumors as well, that will have a
receptor on their surface. That if it binds to
estradiol, for example, it will stimulate the
growth of that tumor. It’s very easy to test for. If you get a tumor a
doctor will likely do a test to see and one of the
questions they will ask is is it estradiol sensitive
or estrogen sensitive. If it is then they
have a tool to work on. The tool is they give
a person who has a tumor that’s estrogen-sensitive, they
give them aromatase inhibitors. That stops the production
of female sex hormones and literally starts starving the tumor. The tumor responds to it. You take it away the tumor doesn’t have the same stimulus that it had before. It becomes much more treatable. So this can be used
after removal of a tumor so if you’re worried
about other similar cells being present in the body
an aromatase inhibitor can be very useful in that regard. Will this cause a person to
go through menopause, female? Yes it will. Yes it will. Cholesterol’s an important molecule. I’m not done with it yet. The last thing I’ll talk about
with cholesterol synthesis is synthesis of another steroid. We don’t always think about
it as a steroid but it is. In fact, in general we talk
about steroids as derivatives from cholesterol, things that
are made from cholesterol. And vitamin D is a
steroid in that category. Vitamin D is made from cholesterol. Here’s 7-dehydrocholesterol. That is a precursor of vitamin D. Vitamin D as you can
see comes from this. Ultraviolet light plays a
synthesis in pre-vitamin D. One of the reasons I
recommend you get some sunshine is so that your body can
naturally make vitamin D. You can get enough vitamin
D with just a few minutes of sunshine a day just by this process because ultraviolet light
can make this pre-vitamin which your body can convert to this and this spontaneously
forms the active form of vitamin D known as calcitriol. If you give the body
this, you’ve got that. So to get to this you’ve got
to have ultraviolet light. If you’re not getting
enough ultraviolet light then you probably need to
take a vitamin supplement. And vitamin D is a vitamin
that we’re finding increasingly that people are very deficient in. Very deficient in. I take a vitamin D
supplement for example because I found out I was vitamin D deficient, and vitamin D is important
for healthy bones. It’s necessary for the proper absorption of calcium and phosphate
from your digestive system. If you’re low in vitamin
D your absorption can have all the calcium you want in your diet but it’s not going to make it in. You’re going to have weak bones. Now it’s very important,
especially for young women, to get plenty of vitamin D. Because what happens is
you develop osteoporosis, fragile bones. You only see them when you’re
sixties, seventies, eighties. You starting developing it now. Right now. If you’re not getting
sufficient vitamin D right now you won’t know it but you’ve
already started yourself on a path that leads to osteoporosis. “I take plenty of calcium.” You can take all the
calcium in the world and it’s not going to do you any good if you don’t have vitamin D. So get your vitamin levels checked. Get sunshine. And if you need to, take a supplement. And the supplement bypasses
that ultraviolet light requirement because the
supplement comes in this form. Word to the wise. Okay, believe it or not
I’m done with cholesterol. And I have about ten minutes to get into fatty acid oxidation
unless there are questions. Are there questions
before I move forward? Yeah, Jerry? Student: [inaudible] Kevin Ahern: Excess
vitamin D is not good. So you don’t want to
overload on vitamin D. It’s not the same as vitamin A. Vitamin A will kill you
if you have too much. But you don’t want to have too
much vitamin D, that’s right. So you don’t just want to go out and start gobbling vitamin D. And that’s why I recommend you
getting your vitamin D levels checked and then periodically
having them checked. But if you’re feel like, oh,
I’m not getting enough sunshine and I’m not getting
out as much as I should and maybe my levels are low,
a little bit would be okay. Connie? Student: [inaudible] Kevin Ahern: In general
you do have plenty of the pre-vitamin D
levels in your body, yes. And that actually makes
me think of another point. People with dark skin will
tend to have more difficulty making this because the dark
skin blocks that to some extent. So people with dark skin who live in northern latitudes like here. Like Indira, for example, had
her vitamin D levels very low. My wife is from India and
her light levels were very low and she gets a fair
amount of sun and so forth. So that is a factor but yes you… I forgot what your original
question was, but… Student: [inaudible] Kevin Ahern: Oh the pre. Right, you have plenty of the pre. Student: [inaudible] Kevin Ahern: Is vitamin D
more essentially than calcium? No, you have to have
both because without, I mean if the question is,
“Should I take vitamin D? I don’t take any calcium. Am I still going to get osteoporosis?” and anytime you have a
limiting amount of material to make bones you’re
going to have problems. So I wouldn’t say that
you can take vitamin D and not consider your
calcium levels, no. I think you should factor
that into it as well. Student: Don’t they fortify
most milk products with that now? Kevin Ahern: Do they
fortify most milk products with vitamin D? They do in many cases. Many people don’t drink milk
so that’s also a consideration. But it pays, it seriously pays
to have your levels checked because what we’re finding,
not we, because I don’t do it, but what people are finding
that vitamin D levels of all the vitamins are probably the one that’s most likely to be low in you. So it’s a real concern,
especially in young people. So young people get out there. Other questions? Let’s get started on fatty
acid oxidation, at least. Try to keep us reasonably
on schedule here. And it was a lot of material today. Fatty acid metabolism is
actually fairly straightforward. What you’re going to see as I
talk about fatty acid metabolism is that the pathway of
synthesis is very much like the reversal of the
pathway of oxidation. There are differences but the chemistry of it is almost identical. The chemistry of synthesis
is almost identical to the reverse of oxidation. So we focus first on the fatty acids, how they’re produced from fat, and then we’ll turn out
attention to oxidation. Fat, by the way, in the body is stored in specialized cells called adipocytes. That’s an adipocyte full of fat. Fat is, remember, water-insoluble
so it’s not surprising the body has specialized
tissues to handle fat, and again those are called adipocytes. What we’re going to be
talking about mostly on Monday, I’ll talk about it briefly
today is the process of oxidation versus synthesis. If we look at the two processes
on the left we have oxidation. And that starts at
the top and goes down. On the right we have synthesis and that starts at the
bottom and moves up. And if you look at the chemistry, and I’m going to just talk you
through it very briefly here, we’ll look at this more closely later, we see that they are very very similar. Here’s a saturated fatty acid. Here’s a saturated fatty acid. This is an endproduct,
this is a starting product. To go from here down
to here involves removal of hydrogens and electrons
from between two carbons. We saw that in the succinate
dehydrogenase reaction. Now we see it in fatty acid oxidation. Look at that. Make a double bond. By the way, one of the
things you’ll notice in these two pathways
that’s completely uncommon is all the action between
carbons two and three. Carbon number 1 being here,
carbon number two being here, carbon number three being there. All the action is between
carbons two and three. Everything happens between
carbons two and three. We make a double bond going down. Looking at this going upwards
we reduce a double bond. This is an oxidation. This is a reduction. Next step, we add water. That’s just like when we went from succinate to fumarate, right? Succinate to fumarate we added water. That got that OH on there and that’s what we’re doing right here. It goes on carbon number three. And this guy we have dehydration. We’re taking water away
to make that double bond. We oxidize that OH going
down to make a ketone. We reduce a ketone
going up to make that OH. In the last step we do what’s
called thiolytic cleavage meaning we use an enzyme
called thiolase to break that bond between carbons
two and three again. That gives us a two-carbon
piece known as acetyl CoA and a fatty acid that’s two shorter. If we’re synthesizing it,
that’s one exception here. If we’re synthesizing we
actually start with a three-carbon piece and we’ll talk about that later. But basically this process is
the reverse of this process, at least from a chemical perspective. Very very similar to
being opposite directions. Yes sir? Student: Are the carbon
three intermediates right there’s stereocenters inverted? Kevin Ahern: Stereocenters are inverted. So structurally they’re different, and I’ll talk about that later. But in terms of
chemistry that’s happening here it’s simply reversal. Well before we finish today
I want to say a little bit about how we get fatty acids
and that’s, well let me see. Actually I’ve got a couple minutes. We’ll see how that goes. Alright there’s glycocholate. Where did you just see glycocholate? Bile acid, right? And necessary to emulsify fat. We have fat in our digestive enzymes. I’m sorry, we have fat
in our digestive system. And we have enzymes both
in our digestive system and in our cells that
will break down fats. They’re called lipases. Some lipases are extracellular. Some lipases are intracellular. What you see happening on the
screen here are extracellular. I’ll show you an intracellular
one here in a second. It does very similar stuff. But lipases use water to
clip fatty acids off of a fat. You start with a triacylglycerol, you clip off a fatty acid,
you’re left with a diacylglycerol. You take a diacylglycerol,
you clip off a fatty acid, you’re left with a monoacylglycerol. And I’m sure you can
figure out that if you take the monoacylglycerol and you clip off a fatty acid you get glycerol. As I said these can happen
extracellularly or intracellularly. Something curious happens
with the absorption of fat. Here’s fat. Here’s that Big Mac that we ate. It’s coming down our digestive system. We’re right in our
digestive system here, in our intestines. Here’s fat. It’s gotta get from the intestine out so it can be packaged up
as chylomicrons, right? How do we get it out? Do we just push it out? It turns out we don’t. First we do that thing
I just showed you. The lipases break it
down into fatty acids and monoacylglycerols. Why do you suppose they
break it down first? It turns out what they
do is they reassemble it once they get across. Any thoughts about
why that might happen? What do fatty acids do? Student: [inaudible] Kevin Ahern: Regulation
would be a good guess but it’s not the right one. Fatty acids act as
detergents, don’t they? It’s actually the fat
that’s being broken down to help emulsify the
remainder of the fat to get it across the membrane. Once it’s gotten across
the membrane it’s saying, “Okay now we’re ready to handle you. “We’ve built you back into
a fat and now we’re going “to put you into a chylomicron.” So they’re broken down to fatty acids plus a monoacylglycerol. They’re put together over here and then built into a chylomicron. So we’ve gotten fat out
of the digestive system and into our body. Inside of fat cells, fat cells
have their internal lipases that will break down,
do the same reaction. Here’s a triacylglycerol. It’ll clip off all
three of the fatty acids and those three fatty acids can
be dumped into the bloodstream where they get picked
up by which protein? Pop quiz? Which protein carries fatty
acids in the bloodstream? I just talked about it last time. You guys were thinking about the exam. You weren’t thinking
about this, were you? Serum albumin. Serum albumin carries fatty acids. Why do we need a protein
to carry fatty acids in our bloodstream? Fatty acids act as detergents. Do we want detergents floating
around in our bloodstream? We don’t. I think we are at a stoping point. Let’s stop there and we’ll see how this is regulated next time. [class murmuring] [END]


19 thoughts on “#36 Biochemistry Cholesterol in the Body Lecture for Kevin Ahern’s BB 451/551

  1. great lecture thx for uploading (esp for ppl wanting to understand heart disease)….. also his shirt color matches his skin and sometimes it looks like he is nude lol

  2. Same syllabus at UEA in Norwich too. I guess biochemistry doesn't differ that much from place to place!

  3. Hi, have you heard about Fat Blast Factor? (search for it on google) You will learn about the serious crimes we commit against our bodies. With Fat Blast Factor, you will discover how to melt fat fast

  4. You are very thorough and non-boring lecturer!!! i am currently taking an online biochemistry course paying way too much money for lectures that are just read by a lecturer from a paper, it is the worst thing i have ever experienced as a student!
    Your lectures are very easy to understand, you repeat things (much needed when a student is learning new material) and make it fun and easy to grasp the concepts! Thank you!

  5. Great! Thank you for the info! My course is almost done but I will be passing along your info to everyone is who will be taking biochem that's for sure!

  6. You talked about recycling of cholesterol by reabsorption in the intestines and that there is a drug to slow that down so that more cholesterol is excreted. It might be helpful to tell your students that cholesterol in the intestines binds to fiber so if they eat their oatmeal their cholesterol levels will go down! You have an opportunity to help your students live healthier lives…

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