Kevin Ahern: Okay
folks, let's get started.
[class murmuring]
Day before the exam.
At least the class day
before the exam, you know?
Let's see.
So I am doing a review
session tonight at 7:30
and that will be at ALS 4001.
I will videotape that
and I will get the video
posted as quickly as I can.
That's one.
Number two, the material for
the second exam starts here.
So everything I'll talk about
today will be on the second exam,
and since we're a little behind
then the second exam's
probably going to have
more material on it than the first exam.
So be aware of that.
Think ahead.
And, that's basically where we are.
So, I want to spend some time now,
we're going to go back and
start talking about metabolism.
Metabolism, of course,
the biosynthetic pathways.
We've seen now how all
the energy considerations
are done with respect
to respiration and so now
we're going to see how that
energy is used to make molecules.
And how we make them and
how we break them down.
For today's lecture almost
everything I'll be talking about
is how we make them.
We don't spend a lot
of time talking about
breaking down of the molecules
that you will see today.
We've talked about glycerophospholipids
and we've also talked about fat.
And it's important to understand
a bit of their metabolism.
So if we think about,
that's a little bit loud,
glycerophospholipid biosynthesis,
not surprisingly the starting molecule
is a molecule of glycerols,
specifically it's a molecule
of glycerol-3-phosphate.
And glycerol-3-phosphate gets
two fatty acids put onto it.
Usually the first fatty
acid at the top is saturated
and usually the second
fatty acid is unsaturated
although that's not an absolute thing,
but that's a general
tendency for the fatty acids.
And the third position of course
is occupied by the
phosphate that we saw here.
The molecule you see on the screen
at the bottom is called phosphatidate,
or as you're more likely to call
it probably phosphatidic acid.
Phosphatidic acid is an
important intermediate
in the synthesis of the
phosphatidyl compounds
which I'll show you in a
minute, and also for making fat.
So if we want to take
phosphatidic acid and make fat
we need to clip that phosphate
off from this structure here.
And then we put the third
fatty acid onto there
and that creates a fat.
And that's actually shown here.
Phosphatidate cleaves
the phosphates off.
We then have a hydroxyl here.
That gives us diacylglycerol.
You've seen that before.
And we take that third fatty acid,
put it on that position and
we have a triacylglycerol.
And a triacylglycerol
is the same thing as fat.
And by the way, I think
I've said it before
but I'll say it again.
The difference between a fat and an oil
is simply the fact that an oil
is liquid at room temperature
and a fat is solid at room temperature.
So that's really the only
characteristic difference
between them.
Student: [inaudible]
Kevin Ahern: I'm sorry?
Student: Do we need enzymes [inaudible]
Kevin Ahern: I did not
give you any enzymes
and when I don't give you enzymes
I'm not expecting you to know them.
Now, I'm going to talk
about the synthesis
of some glycerophospholipids,
some phosphatidyl compounds.
And you'll see that there's a
fair amount of information here.
And again I want you to
see big picture on these.
The big picture is that
we have starting molecules
like phosphatidic acid and we
attach various things out here
to the phosphate on the side.
As I noted earlier on the last one
I'm not expecting you
to know enzymes for this,
but just big picture.
If I were to make a
CDP-diacylglycerol, for example,
how would I make it?
Well this guy right here
turns out to be an important
intermediate in the synthesis
of glycerophospholipids because,
and you might begin to
see the pattern here,
it is an activated intermediate.
An activated intermediate you remember
is a molecule that
has a high energy bond
and it uses the energy of that bond
to give a part of
itself to something else,
or attach a part of
itself to something else.
So we're going to see
this CDP-diacylglycerol
is used to make the
phosphatidyl compounds,
and that's coming up.
That's a nice structure.
If we were to take CDP-diacylglycerol
and swap out the CDP for inositol,
we would make phosphatidylinositol.
And then, again, here is
that activated intermediate
that is using the energy
of this bond right here
to transfer a part of itself,
which is this black part over here
to this green guy over here.
The result of that is we're
making a phosphatidylinositol
and this is the root
molecule we talked about.
We talked about about
PIP2, PIP3, and so forth.
This is PIP.
Actually it's not even PIP
because it doesn't
have a phosphate on it
but it's phosphatidylinositol.
If we put phosphates onto
any of these OH's out here
we would create PIP,
phosphatidylinositol phosphate.
And PIP, you may remember,
was used for signalling.
Now in the process of making this
you'll notice that one of the phosphates
of the CDP-diacylglycerol
is left behind.
That means that what
clips off is actually CMP,
cytosine monophosphate, and
this pattern is very common
that we use for synthesizing
all of the various
phosphatidyl compounds.
Here is diphosphatidylglycerol.
It's kind of an odd one.
And we can see over here,
here's that phosphatidyl part
with a phosphate.
Yet over here is also a
phosphatidyl with a phosphate.
That's the diphosphatidyl part.
And in the middle is a glycerol.
Now this is a rather unusual compound
and it's also called cardiolipin
which tells us a little
bit about where we find it.
This unusual glycerophospholipid
is actually found
predominantly in heart tissue.
Now, there are other
pathways that we can use
to synthesize phosphatidyl compounds,
and you can see some
of them on the screen.
For example, if I wanted to
make a phosphatidylethanolamine
I would do it by this pathway here.
Again, don't sweat the details too much.
We're simply making an
activated intermediate here,
phosphorylethanolamine, alright?
And then we're taking that compound
and combining it with CTP to make a CDP.
And then, let's see here we go.
I have a figure for that.
So here's our ethanolamine.
Here's phosphorylethanolamine,
so we're making an
activated intermediate.
There's that high
energy bond right here.
This is CDP-ethanolamine.
We swap out the CDP.
In this case we're putting
a diacylglycerol on it
and making phosphatidylethanolamine.
So we can do that activated
intermediate in two ways.
One is we can link the CDP
to the phosphatidyl part
and then transfer the phosphatidyl
part to something else,
or as you see here, we can take and link
the thing that's going to be
attached to the phosphatidyl part,
in this case ethanolamine,
and we create an activated intermediate
that transfers the ethanolamine
to the diacylglycerol.
The net product is the same.
Now I'm not expecting
you're going to go say
which ones go with the activated
intermediate with CDP first,
and which ones go with
the other one first.
That's not the important thing.
The important thing is that we're
using activated intermediates
in the process of synthesizing
phosphatidyl compounds,
and for our purposes we
will just think about them
as we can link the CDP to
the phosphatidyl compound
or we can link it to the other one.
The net result is we get
a phosphatidyl compound.
So this is how we making
phosphatidylethanolamine.
That's how we make phosphatidylserine.
That's how we make
phosphatidyl-you-name-it.
There will always be an
activated intermediate
involved in that process.
Now I'd also like to sort of
stop and think at this point
about some important considerations
relative to nucleotides
because you've now seen nucleotides
being involved as
activated intermediates
in a couple of ways.
You've seen it-UDP-glucose for example
was an activated intermediate.
You saw that, here, CDP is used
as an activated intermediate.
There are other places
where ATP actually is used
and some places where GTP is used.
We're not going to go
into those right now
but I point out that two
major categories of metabolism
involve activated
intermediates with nucleotides.
What this means is that
nucleotides are very much necessary
and they're also used to
measure the pulse of a cell.
If we don't have enough CTP
we're not going to make
glycerophospholipids.
If we have an abundance of CTP
we very well may be making
glycerophospholipids.
And that's important because
if a cell is to divide
it's going to need glycerophospholipids.
So just as we thought of
the energy needs of a cell
with respect to
division, ATP for example,
so too can we think of
the other nucleotides
as being necessary for a very
important cellular function.
When we talk about the
phenomena of translation
later in the term we'll see that GTP
is actually the energy
source for translation.
So all four nucleotides
have very, very intimate
and intricate roles in metabolism
apart from their being
involved in DNA and RNA.
So that's a very, very important point
when we think about
the overall metabolism.
And there's phosphatidylcholine.
This one's a little bit unusual
in the sense that to
synthesize phosphatidylcholine
we actually start with
phosphatidylethanolamine,
and the difference between
phosphatidylethanolamine
and phosphatidylcholine
are three methyl groups.
You see them up here in green.
And the three methyl groups
are donated to the molecule
by a methyl-donating molecule
that's common in the cells
known as S-adenosyl methionine
or, as you're welcome to call it, SAM.
S-A-M.
S-adenosyl methionine is a very
common donor of methyl groups
in metabolic processes.
We'll see other ones later.
The product of that
gives us the methyl groups
onto the target molecule
and the by-product of that
is S-adenosyl homocysteine.
If we want to take that S-adenosyl
homocysteine and use it again
then that means we need
to recharge the methyl
group back on there so it can be used
as a S-adenosyl methionine
for something else.
So that's basically what I want to say
about glycerophospholipid biosynthesis.
I'm really not going to say much
about glycerophospholipid degradation
until I talk about fat metabolism later.
Sphingolipids are,
as you've seen before,
interesting and odd structures.
They look rather unusual
but as I pointed out to you
when I talked about
their structure before,
I pointed out to you
that when we look at them,
their shape overall, they
don't look very different
from a regular phospholipid
once they've been made.
One of the primary differences
we saw in the sphingolipids
was that the sphingolipids, A,
will frequently have
carbohydrates in them.
So we saw that, for example, a
cerebroside had a single molecule
of sugar in it, might be
glucose, usually glucose,
where as a ganglioside would
have a complex mixture of sugars
connected to it in an oligosaccharide.
And the other difference that
we saw with the sphingolipids
was that they were usually not present
in a phosphorylated state.
The prime exception to
that was sphingomyelin
which I said was a
sphingolipid commonly found
in neural membranes.
Well sphingosine is
what we sort of think of
as a starting material.
It's technically not a starting material
but it looks like a starting material
so for our purposes
we will call it that.
How do we get to sphingosine?
Sphingosine actually,
or at least the
sphingolipids that we make,
are actually made by combining
two very common things
that we find in cells.
And the two common
things that we combine
are the amino acid
serine and the fatty acid
known as palmitic acid.
So we put those two together
and we can make a sphingosine.
Now you'll notice if
you look at this equation
that we make dihydrosphingosine
which is why I said
we don't directly make sphingosine
but sphingosine looks like
it so there's the reaction
if you want to go
through all the reaction.
There's palmitoyl CoA.
That's palmitic acid.
Plus serine gives us blah
blah, blah blah, blah blah.
There's the dihydrosphingosine.
Again I'm not expecting you're
going to know this or know this.
If you know sphingosine
I'm happy with that.
But from sphingosine forward
I think you should have an idea
about what's happening in the
synthesis of these sphingolipids.
If I take a dihydrosphingosine
or in our case sphingosine
and I say, and I add to
it a single fatty acid,
I create something known as
a ceramide, C-E-R-A-M-I-D-E.
I think in the highlights from
before I've mentioned ceramides
but I didn't talk about them in class.
Here I'm letting you know what
they are and how we make them.
So this guy here comes from
palmitate-palmitoyl CoA and serine
and we make a dihydrosphingosine
which gains another fatty acid.
When it gains that fatty
acid we have a ceramide.
A ceramide is really a branch
point between the synthesis of
a ceramide there, the ceramide here.
I'm not speaking very coherently, am I?
Ceramides are actually branch
points for the synthesis
of the other sphingolipids.
We can make sphingomyelin from ceramide.
We can make a ganglioside from ceramide.
We can make a cerebroside from ceramide.
So ceramide's a very
important branch point
for the synthesis of
the other sphingolipids.
Yes sir?
Student: [inaudible]
Kevin Ahern: I'm sorry?
Student: Is that because the ceramides
now have that more
reactive carbonyl group?
Kevin Ahern: They do have a
more reactive carbonyl group
that can play a role, yes.
Now here's my ceramide.
If I take and I put on a,
basically a phosphocholine
from this process here
I make sphingomyelin.
If I take the ceramide
and I put a glucose on it
from UDP-glucose I
can make a cerebroside.
And if I were to take that cerebroside
and add some additional sugars
onto that I can make a ganglioside.
So again, no enzymes here.
We're just talking very
simple schematic type
of biochemical reactions.
This is a schematic
representation of a ganglioside.
There's our ceramide base.
There is a complex
oligosaccharide out there.
That's glucose, that's galactose.
That's neuraminic acid right there.
That's galactose.
That's N-acetyl galactose.
And no I'm not expecting
that you're going to be able
to draw that so don't sweat it,
but you should know
obviously that a ganglioside
has a complex
oligosaccharide present on it.
And it varies tremendously
from one ganglioside to another.
That's a nice picture
of lipids in a lysosome.
And I won't say more about that.
The important thing that I
like to point out at this point
is that deficiencies in enzymes
necessary for breaking down
some of the complex
sphingolipids that we have,
enzymes deficient in
breaking those down,
so if we have a person
who has a genetic disorder
where they're missing
an enzyme necessary
for some of the breakdown of these
can have some very severe
neurological problems.
Tay-Sachs disease is one disease
where people who have it
are lacking an enzyme
that simply takes off,
this guy off the end and
makes this guy over here.
And again I'm not worried
if you know GM2 or GM3,
that's not really the important thing.
But very simple lack of enzymes lead to
in some cases severe
neurological symptoms.
Remember that these are things
that are commonly used in brain
and neural tissue and so an
inability to process them properly
leads to abnormal function,
or abnormal structure
of neurons in brain tissue and
can cause some severe problems.
So I know I'm moving
fairly rapidly through that
so I'll slow down a bit and
first of all take questions
and then move on to
cholesterol biosynthesis.
So, questions?
Nobody wants to think about
this until after the exam, right?
So again, I want you to look
at this as the big picture.
I want you to think about it in
very general terms and, yes sir?
Student: [inaudible]
Kevin Ahern: Ceramide, yeah.
Student: [inaudible]
Kevin Ahern: You don't need
to know structures here.
You don't need to show me where
they're going on the molecule
if that's the question.
But you should know that to go
from a ceramide to a cerebroside
that I would need glucose.
And I think it would be useful to know
that glucose comes from UDP-glucose.
But where that's going to
be attached on the ceramide,
that's not really
necessary for our purposes.
You like that?
Student: [inaudible]
Kevin Ahern: Okay, well we
don't tend spend a lot of time
in biochemistry talking about
glycerophospholipid metabolism
or sphingolipid metabolism,
and they are important,
especially as we look at
sphingolipid metabolism
because as I said there are
some very severe neurological problems
that are known for people
lacking certain enzymes.
So it's probably an unfortunate thing
but it's not something that
we have much time to spend on.
What I want to spend some
time on though is talking about
the synthesis of cholesterol.
And I also want to talk about
the movement of cholesterol
in the body because this,
both of these are pretty
interesting phenomena.
Cholesterol biosynthesis
is actually fairly simple.
Cholesterol's a fairly complex
molecule but what we discover
is that in the synthesis of cholesterol
we start with very very
simple building blocks
and we make bigger building
blocks that we start assembling.
And I'll show you how
this goes and you'll see
it's not really overly complicated.
This shows us the
structure of cholesterol.
And one of the things that the
figure is trying to show you
by using the red and the
blue is to show you the source
of all of the carbons in this molecule.
It turns out that all the
carbons in this molecule
can come from this
acetyl group over here.
Acetyl CoA is the precursor of
the entire cholesterol molecule.
We can trace every carbon back
to whether it was a methyl carbon
or a carbonyl carbon in
the original acetyl CoA.
So even though this looks pretty
hairy, and it is sort of hairy
I'll be honest with you,
we have very neat and
relatively simple ways
of putting these together.
So let's take a look at
how this process occurs.
Now we'll come back and we'll talk,
you'll actually see this
figure later in the term
when I talk about the
synthesis of ketone bodies
because this path overlaps
with ketone bodies,
but we're going to focus
right now on making cholesterol
and that means we're going to focus
on everything that
happens in the top part.
We're not going to delve
into the stuff in yellow.
So if we want to make a cholesterol,
how do we get started in the process?
The way that we get started
is by starting with
a four-carbon molecule
known as acetoacetyl CoA.
How do I get acetoacetyl CoA?
Well if I take two acetyl
CoA's and I put them together
and kick out one of the CoA's
I end up with acetoacetyl CoA.
So this guy is made originally
from two acetyl CoA molecules.
So now you can see we're going to add
a third acetyl CoA molecule,
which is shown in red there,
and when we do that we make
something that has six carbons.
This guy right here with six
carbons has a mouthful of a name
and you're much more likely
to be like me to learn it
by its abbreviation, HMG-CoA.
Hydroxy-methylglutaryl CoA.
Now, the enzyme that
catalyzes this process,
I'm getting ahead of myself,
the enzyme that catalyzes this process
is not really important
for our purposes.
But what is important for our purposes
is the next enzyme in the process.
The enzyme that converts
HMG-CoA into mevalonate
you'll notice is doing
something kind of funky.
There's two NADPH's and NADPH
is used commonly to make molecules.
It is a source of electrons.
So we're going to have to do a reduction
in going from HMG-CoA to mevalonate.
It's going to take two reductions.
That is a total of four
electrons to make this happen.
And in the process CoA's
going to get kicked off.
Now this enzyme that
catalyzes this reaction
is a critically important enzyme
for human health consideration.
This enzyme is known
as HMG-CoA reductase.
HMG-CoA reductase.
That's one enzyme I definitely
expect that you will know.
Why do I expect that you will know it?
Well for one thing, this
enzyme is feedback inhibited.
And it's feedback
inhibited by the end product
of this pathway which is cholesterol.
So as your body is making cholesterol,
and that's what we're starting here
is the process of making cholesterol,
if it gets too much and
makes too much cholesterol,
cholesterol will feedback and
inhibit the enzyme and say,
"Quit making so much cholesterol."
Now this is very important
because as we will see
the pathway to make
cholesterol is very long
and it requires a hell
of a lot of energy.
So we don't want to be making
cholesterol if we don't need it,
and so as the cholesterol
levels start to rise
this enzyme gets shut down.
Now this enzyme is also critical
for another very important purpose,
and as you might expect it's
a very good target for a drug.
So people who have
high cholesterol levels
that aren't manageable by
other means such as diet,
and I'll talk about that in a bit,
take drugs known as
statins, S-T-A-T-I-N-S.
And statins inhibit this enzyme.
Statins inhibit this enzyme.
And they're very effective
at turning off this enzyme.
You can really change a
person's cholesterol levels
significantly by treating
them with statins.
The most commonly used
one is called lovastatin,
L-O-V-A-S-T-A-T-I-N,
and what these drugs do
is they mimic HMG-CoA.
The enzyme binds to them but
it can't do anything with them.
If the enzyme gets occupied
the enzyme therefore isn't catalyzing
and cholesterol
biosynthesis goes way down.
So statins are competitive
inhibitors of this enzyme.
They resemble the normal substrate.
Now, if we were to talk
about this lower pathway,
which we will later in the term,
we'll see that this pathway
going down below also
comes from HMG-CoA,
and it leads to the
synthesis of ketone bodies,
and ketones bodies are
important energy sources for us
when we're very low on glucose.
But I'll remind you of that when
we get back to that later on.
Gesundheit.
Now we've gotten to mevalonate.
Mevalonate has six carbons.
It turns out that the
building blocks that are used
to make cholesterol
actually have five carbons.
And schematically we
call them isoprenes.
Isoprene is not a real molecule,
it's a category of molecules.
It's a category of molecules
that have five carbons
that are used to make cholesterol.
And by the way, when you
hear about steroid synthesis
and steroid hormones
and that cholesterol
is the precursor of those.
So this pathway which are
known as isoprenoid synthesis
is important for making
cholesterol and therefore
also important for
making steroid hormones.
So isoprene is a category of molecules.
We'll see that there are two isoprenes
that are used to make cholesterol.
One is isopentenyl pyrophosphate.
And no I don't have a
better name for that.
Oh heck, let's call it IPP.
Why not?
[class giggling]
Let's call it IPP.
Did you like that?
It sounds like I had a bathroom
accident or something, right?
[class laughing]
It just occurred to me.
So isopentenyl pyrophosphate.
How do we get there?
Well we don't care about how
all of these reactions go.
We're starting with a
six-carbon mevalonate
and we're going over here
through a decarboxylation
ultimately to yield
isopentenyl pyrophosphate.
Notice this pyrophosphate, PP.
We might expect that
that is a high energy bond
and in fact it is.
A lot of the assembly of these molecules
involves high energy pyrophosphates
that are needed energy sources
for the overall process to occur.
Look at this.
Just to go from mevalonate to
IPP we need one, two, three ATP's.
And we've only made the first
five-carbon intermediate.
So making cholesterol
costs a lot of energy.
The other molecule that
we use to make cholesterol
is known as dimethylallyl pyrophosphate,
and let's just call
that DMAPP, D-M-A-P-P.
How about that?
Dimethylallyl pyrophosphate
or DMAPP is made from
isopentyl pyrophosphate.
It's simply an isomerization
that is performed.
See we moved that double
bond from here over to here.
And no, you don't need
to know their structures.
You do need to know
they have five carbons.
So we have our two building blocks.
These two guys are
used to make cholesterol
and ultimately all of
the steroid hormones.
So how do we do this?
Here is a rather confusing
way of showing this to people.
I'm not totally keen on
this but I will tell you.
Basically what we're doing
is we're taking two
five-carbon intermediates.
We take one IPP and we take one DMAPP,
and when we join them together
we make a ten-carbon molecule.
The ten-carbon molecule is
known as geranyl pyrophosphate.
This says "either or" and that
depends with what you start with.
But in the simplest
scheme we start with five,
one isopentenyl
pyrophosphate, one DMAPP,
and we end up with one
geranyl pyrophosphate.
Five carbons plus five
carbons gives ten carbons.
If we add another
five-carbon molecule to that,
as shown here in a much better figure,
so here's our starting process,
a five plus a five giving us a ten.
If we add another isopentenyl
pyrophosphate to that,
five, or ten plus five is
going to give us fifteen,
and fifteen gives us
farnesyl pyrophosphate.
If we take farnesyl
pyrophosphate, we take two of those
and put them together
we make a thirty-carbon
molecule called squalene.
So everything that we have has come
ultimately from acetyl CoA molecules
and we've made a thirty-carbon
linear intermediate.
I call it linear because you
don't see any rings there yet.
You're going to see
rings in just a minute.
So we've made a thirty-carbon
intermediate known as squalene.
Squalene is what I describe
as the last significant
linear intermediate.
As we look at that, we convert squalene,
now this is kind of cool.
Once we've got that guy made
we discover that these bonds
can be rotated into a
form that looks not unlike
what cholesterol looks like.
We add some reducing
power of NADPH again
and we make an intermediate
that starts to look
more like cholesterol.
Ultimately it flips into
this configuration down here
known as lanosterol.
Lanosterol is what I describe
as the first cyclic intermediate.
So squalene is the last
linear intermediate,
squalene is the first cyclic.
These guys are sort of
transient in the process.
Now lanosterol looks a heck
of a lot like cholesterol.
It looks a heck of lot like cholesterol
and you might think that in fact
it would be a very simple
case to get to cholesterol,
but in fact it takes nineteen steps.
Would you like to go
through those today?
No.
We've done enough already today, right?
Nineteen steps.
So we're going from this guy above
to this guy below and
you can see some changes.
You can see these methyl
groups, for example, disappear.
You can see there's some
changes in the ring out here.
There's also a change in the
location of this double bond.
But for the most part
they're relatively structural
simple changes but it
takes nineteen steps
in order to get to that
final product of cholesterol.
Now that's the synthesis of cholesterol.
Questions about that?
Everybody's tired, right?
A lot of material today?
Student: [inaudible]
Kevin Ahern: Yeah, why was [inaudible]
Was that a comment or question?
Oh, your hand was just going like that.
Okay how about a song?
[class murmuring]
I've got a song that covers this process
that may help you to learn it.
So, it's to the tune of When
Johnny Comes Marching Home.
It's called To Make a Cholesterol.
Lyrics: Some things that you
can build with acetyl CoAs
Are joined together
partly thanks to thiolase
They come
together 1-2-3
Six carbons
known as H-M-G
And you're on your way
to make a cholesterol.
To synthesize a mevalonate in the cell
Requires reducing HMG-CoA, as well
The enzyme is a reductase
Controlled in allosteric ways
When the cell's impelled
to make a cholesterol.
The mevalonate made in metabolic schemes
Get decarboxylated down to isoprenes
They're built together willy-nil
To build a PP-geranyl
In the cells' routines
to make a cholesterol.
A single step links
farnesyls but that's not all
The squalene rearranges to lanosterol
From that there's nineteen steps to go
Before the sterol's apropos
Which you must recall
to make a cholesterol.
The regulation of the
scheme's complex in ways
Inhibited by feedback of the reductase
And statins mimic so they say
The look of HMG-CoA
So we sing their praise
and not make cholesterol.
Woo.
So that's how we make cholesterol.
What's that?
Student: [inaudible]
Kevin Ahern: No.
The synthesis of cholesterol
is regulated in the cell.
Actually I'll tell you what.
Let me come back to that next time.
I'm going to come
back to that next time.
We're not going to leave early.
I would rather spend our remaining time
talking about the movement
of cholesterol in the body.
So next time I'll talk about
the other regulation that's done
because there are other
important regulation
considerations for cholesterol.
Let's think about a very important
consideration in our body.
And the very important
consideration in our body
is we eat a lot of fat.
We eat too much fat.
But even when we eat too much fat
or even when we eat
just a little bit of fat,
we've got a problem,
and the problem is that
fat is not soluble in water.
Fat is not soluble in water.
We eat plenty of glucose, not a problem.
Digestive system dumps
it into the bloodstream.
Glucose is soluble in water.
It moves in the bloodstream
very rapidly and very easily.
Fat does not do that.
So fat actually takes,
and fat compounds include
things like cholesterol,
so anything that's water-insoluble,
cholesterol, fat, fat-soluble vitamins,
all of these have to be packaged up
so that they can move in the body.
So that's what is the subject
of the rest of what
I'm going to say today.
So these evolve some
interesting complexes
that are called lipoprotein complexes.
So I want to take you through these.
Let's imagine I've eaten
that giant Big Mac double
cheeseburger loaded,
dripping with grease.
So it's loaded with fat.
Or maybe I'm eating a veggie burger
that I dumped a whole bunch
of butter onto, I don't know.
Yum yum, right?
We're going to follow those
water-insoluble compounds
in their movement through our body.
So when I eat that, the
first thing that happens
is these compounds
hit my digestive system
and that digestive system has
the very first thing it has to do
to make them soluble, and it does.
It solubilizes water-insoluble
compounds using detergent.
Just like you use detergent
to clean your clothes,
your stomach uses detergent
to solubilize water-insoluble things.
The detergents have a name and
they're known as bile acids.
Bile acids.
B-I-L-E.
Bile acids are
derivatives of cholesterol
that have some charged groups
that have been placed onto them.
We'll see their metabolism later.
But they've got charged groups
so they act like detergents
because one part of them
is very water-insoluble
and one part of them
is very water-soluble,
just like a detergent is.
They emulsify that fat
to make it water-soluble.
They emulsify anything in
there to make it water-soluble.
I'm going to specifically
focus on fat for the moment
but what I'm saying also is
true for other compounds as well.
Fat first of all has to make
it across the intestinal wall
in order to ultimately make
it into our bloodstream.
And it does that.
There's a scheme that I'll
actually talk about later
but for our purposes at the moment
we'll just say it moves
across the intestinal wall.
And after moving across
the intestinal wall
these water-insoluble compounds
get dumped into the lymph system.
They get dumped into the lymph system.
Now something very important happens
as they're getting dumped
into the lymph system.
They get assembled into the first
of the lipoprotein complexes.
And these lipoprotein complexes
are known as chylomicrons.
So chylomicrons are
lipoprotein complexes.
When I say lipoprotein
complex, what does that mean?
It means that it contains lipids.
It's water-insoluble things.
And it contains proteins
to help hold those.
They're actually big balls of stuff.
The outside are portions that
are the groups of the proteins
that are interacting with water.
And on the inside of these big complexes
are the portions of the
protein that are hydrophobic
and they interact with the lipids.
Well as the chylomicrons are made
they are great big honking complexes
that look like they're
just totally destined
to go plug up your arteries.
And in fact they don't.
They don't.
They pass through your lymph
system into your bloodstream
and they're the biggest and
fluffiest of all of these complexes.
they're quite large.
Their density you'll see is the
lowest of all of the complexes
and these complexes
vary in their density.
So we have chylomicrons,
we have very low density,
we have intermediate
density, we have low density,
and we have high density.
The lower the density
the fluffier, as it were,
that they are, and the size.
They're also the biggest.
They're quite large complexes.
Well these guys are full of fat,
they're full of cholesterol
and they're full of
fat-soluble vitamins.
They're needed nutrients for cells.
Those chylomicrons dump
into the bloodstream
and it's like I said
it looks like they're going
to go plug something up
but they don't plug up
anything that causes problems.
They do plug something up though.
They go and they hit the capillaries.
And when they hit the capillaries
they plug up the capillaries.
Doesn't that cause problems?
No.
The capillaries are
integrated with the tissue
and that tissue is needing the nutrients
that's contained in these chylomicrons.
So it contains nutrients
that are needed in there
and so these tissues
around the capillaries
will secrete enzymes that will
start to break down the fat.
They will start to break down the fat.
They will not touch the cholesterol.
The fat when we break it
down produces fatty acids
and it produces glycerol.
The fatty acids can be taken up by cells
and used as an energy source.
The fatty acids can also be
released into the bloodstream
where they get taken
up by serum albumin.
So fatty acids really can go either way.
Either into the target, into the
cells that are digesting them,
or into the bloodstream
where they're gobbled
up by serum albumin.
Serum albumin is the protein
that carries fatty
acids in the bloodstream
and that's partly because
fatty acids themselves
can act like detergents, and
if you think about detergents
what do they do to the
structure of proteins?
Denature, right?
So if we have something to contain them
and keep them from causing
problems, that's what cells do.
Well after the enzymes
in the target tissues
and the capillaries have
had a pretty good lunch
munching on the fat
in those chylomicrons,
the chylomicrons start to shrink.
And as they shrink and
they shrink and they shrink,
remember that the cholesterol
hasn't been touched
so the cholesterol is still in them,
as they start to shrink they
get smaller and smaller in size.
Ultimately they're small enough
to pass through the capillaries.
At that point they're
called chylomicron remnants.
The chylomicron remnants
have one destination
and that destination is the liver.
So the remnants go to the liver
and they get absorbed by the liver.
So we saw that the liver
played an important role
in sugar metabolism.
Now we're starting to see that the liver
plays a very important
role in lipid metabolism.
The liver absorbs the
cholesterol, the fat,
fat-soluble vitamins
that didn't get taken up
on that pass through the capillaries.
Well how do we get
these other complexes?
This is where the story
gets a little complicated.
The liver is now a bank, as it
were, of cholesterol, of fat,
and of fatty acids.
It's not an infinite reservoir.
It can't take things forever.
It's ability to balance things,
that is to let out cholesterol
and so forth when it's needed
and absorb it when it's eaten,
is partly a function of the
fatty state of the liver.
If we exceed that capacity
then virtually every cholesterol
we eat is going to go
into our bloodstream.
One of the things that your
doctor will try to do with you
if they determine that your
cholesterol levels are too high,
is the very first thing they
do, they will not give you drugs.
They will try to get
you to manage your diet.
Lose some weight and eat less foods
that tend to have cholesterol in them.
Eat less fatty foods as well
because fat is a player in this process.
So those are the things your
doctor will try to do with you.
If your diet can
manage your cholesterol,
that is you can sort of increase
the capacity of your liver
to manage things, then
you don't need drugs,
and any time you can avoid drugs
you're probably in better shape.
That's not always possible
and we'll see some reasons
for why that can happen later.
So if that doesn't work
then the doctor might say,
"Okay, well let's be thinking
about putting you on statins,"
because when we think about cholesterol
we think about how much
you're getting in your diet,
but we also think about
how much you're making.
What we can control pretty
readily is how much you're making.
So if you can't control
diet we'll go statins.
So the liver has all
this cholesterol in it.
How does it get it all back out?
The liver has to understand
what the body's needs
are for cholesterol.
So first of all I'm going to
tell you what the liver does
to put cholesterol out into the body.
The body, the liver's getting a signal
which I'll describe in a bit,
and that signal is telling the liver,
"Hey we need some help out here.
"We need some fat, we
need some cholesterol,
"we need some vitamins."
The liver says, "Okay, I've
got plenty sitting here.
"I'm going to package it up into
very low density lipoproteins."
So the liver makes a new complex.
They're called VLDLs.
And these guys are fairly large also.
And they are very fluffy.
And these guys don't
cause heart attacks either.
VLDLs are not really a
problem in the overall scheme.
What do VLDLs do?
Well they go out to target
tissues and guess what?
They get stuck and they
get attacked by enzymes
just like the chylomicrons were.
And some of the fat gets dissolved.
Some of the fatty acids get taken.
Some of the fat-soluble
vitamins get taken.
But none of the cholesterol.
Cholesterol does not make
it into cells through VLDLs.
As the VLDL starts getting
its insides eaten away
it starts shrinking in size.
It becomes an intermediate
density lipoprotein.
And these are less
fluffy, they're less big,
but they're not really a problem either.
Only when we've gotten all
the way down to the LDL state,
the low density lipoproteins
do we start thinking about
problems with cholesterol.
Why?
Well first of all,
cholesterol concentration
is highest in the LDLs.
The cell has been taking
fat and fat-soluble vitamins
away from these complexes
but it hasn't been
touching the cholesterol.
So relatively speaking, the LDL
has the highest cholesterol within it.
So LDLs are bad, no?
Well your doctor will probably
describe it as bad cholesterol
but LDLs have a very
important role in our body,
and the role that they have
is that they are the delivery mechanism
to get cholesterol directly into cells.
How does that happen?
Student: It gets in by endocytosis.
Kevin Ahern: It gets in by-oh
she's answering the question.
It gets in by endocytosis.
There's a receptor on the
cell that binds to LDLs.
It grabs them and it internalizes them.
The entire LDL gets gobbled up by cells.
The cell gets everything
that's in it at that point.
Whatever fat's leftover,
whatever fat-soluble vitamins,
and the cholesterol that's there.
Now I'm almost out of time
but I'm going to finish
with one more thought
and then I'll pick it up next time.
How can we tell how much the cells need?
The liver can tell it by looking
to see how many LDLs
make it back to the liver.
The more LDLs that make
it back to the liver,
the less got taken up.
The cells must be happy.
The more LDLs get taken
up, the liver says,
"Oh wow, they ate up
everything I put out there.
"I'd better put out some more."
Just like a mother feeding her kids.
If the kids eat everything
maybe I need to give them some more
because they need some more food, right?
So if the LDLs coming back to
the liver are low the liver says,
"Gotta put more out."
That's a good stopping point.
Let's stop there and we'll
talk about this more on Friday.
[class murmuring]
Oh by the way, when you come
and seat yourselves next time,
seat yourselves like
we did last term, okay?
Row one, row one, row one.
[END]
