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Good morning. Good morning,
yes, thank you. Well, we were

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coming to the end of the
term rather soon. That's sad.

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And, what I'd like to do today is,
picking up on some of the stuff that

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Bob has been doing, begin
to show how the things we've

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learned about understanding
molecular biology,

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biochemistry, genetics, all
come together to help us treat

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disease. That is after
all the point of all this.

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Bob spoke about this with respect
to cancer. Today my goal is to talk

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about this with respect to heart
disease. We've got about 50 minutes

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or so, and I'd like to see if we
could solve heart disease by the end

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of the period. That seems
like a reasonable goal.

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And so, I would like you,
by the end of today's class,

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to design a therapy to cure most
people or at least to prevent a

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couple million heart attacks,
all right? So, that's our goal.

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So, we'd better get to work if
we're going to accomplish that in

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the allotted time. So,
first off, you need to know a

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little something
about heart disease.

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The heart: that's obviously an
important component of understanding

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heart disease.
What's the heart do?

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The heart pumps blood, and
to and from tissues providing

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nutrients, hormones,
removing waste products,

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cells, for example, it pumps
around red blood cells and

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white blood cells and things like
that, and of course oxygen in the

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blood. These are incredibly
important things that your heart

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does. If your heart should stop
doing it for even relatively brief

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periods of time,
it's very bad news.

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This is extremely serious not
to have your heart pumping,

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as you all know. One of
the ways in which you run

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into trouble with your heart pumping
is if the vessels that carry blood

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away from the heart to the
periphery arteries become clogged.

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Just simple plumbing problem here:
if they become clogged and the

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arterial wall gets build ups
here, we have what is called

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arteriosclerosis. And,
it can lead eventually to

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nearly complete blockade of
a vessel. And if that vessel,

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for example, were to be supplying
something important like,

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for example, the blood supply
to the heart muscles itself,

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that would be extremely bad, all
right, because then your heart

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muscles wouldn't have oxygen,
and they would quickly die.

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Other problems can happen here too,
where you could have insufficient

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blood supply to the brain.
What happens when your brain

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doesn't get enough oxygen: stroke.
So, we have many, many of these

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issues. So, if it's the brain:
stroke. If the tissue that doesn't

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get enough oxygen is the heart,
you've got enough heart attack.

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And so, we want to prevent this
process of the buildup of plaques in

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the arteries. And these plaques
are made up of complex mixtures of

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proteins, lipids, and
cholesterol, and surely by now

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you all know that cholesterol
was this evil molecule,

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and it will indeed be the
villain of today's story.

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So, that's the basic plan there.
I'll draw your basic plumbing

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diagram here just so you have it.
We've got a heart here. This is

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your heart, somewhat simplified
picture here. The heart pumps blood

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that goes out to the body, to
the heart itself, to the brain,

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and of course this before it's
doing it is receiving oxygenated

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blood from the lungs. So,
it's really all of these places

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that we're trying to keep flowing.
The number of heart attacks, deaths

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from heart attacks, and other
cardiovascular disease is

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extraordinarily high.
It's on the order of 1.

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million deaths per year. By
contrast, number of deaths from

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cancer is about 600, 00
or so, something like that.

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And, this has been coming down
a little bit for cardiovascular

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disease partly because of some of
the things we'll talk about today.

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But it still is a leading
killer of adults in this country,

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and indeed the leading killer
of adults in this country,

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although there are projections that
cancer may take over in that role.

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Heart disease is
incredibly important. So,

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if we're going to try to understand
how we're going to prevent these

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plaques, and I've told you already,
and you know from the media that

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these plaques have lots
of cholesterol in them,

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and that you all know that
high cholesterol is bad,

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how do we know that
high cholesterol is bad?

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Correlation. Epidemiological
correlation is one,

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and as we will see today, there
are some other, more direct

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results coming out of genetics
that point to this as well.

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What is cholesterol? Let's
talk about cholesterol.

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So, this is
the structure

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of cholesterol.

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There we go. That's cholesterol.
It's a very complex, interesting

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molecule here with lots of rings.
It is a waxy substance. If you

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were to look at a test tube
with a lot of cholesterol in it,

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it would look like wax. And,
it is extremely hydrophobic. It

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will not dissolve in water. So,
if cholesterol is such an evil

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molecule as you all know from
the news media, why do we have

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this evil molecule?
Sorry? Well, because it's

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absolutely essential for life. I
mean, despite it's rep as an evil

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molecule, it's extraordinarily
important. The uses of cholesterol

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are many. One you've already said.
It plays a structural role in cell

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membranes, the plasma membrane.
This is not a big player role in the

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cell membrane. But about
half of all the lipids in

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the cell membrane are cholesterol.
It's a huge component. Cholesterol

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molecules, because of their funny
shape, helps stiffen membranes and

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strengthen membranes. So they
strengthen and stiffen the

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membrane. Also, not
only are half of the

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lipids in your cell membranes
cholesterol, half of the cholesterol

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in your body is in
the cell membranes. So,

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that's the major location.
They're also used, these complex

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molecules, as precursors for the
synthesis of steroid hormones.

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Steroid hormones, of course,
also are evil these days.

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Those of you who checked the New
York Times today saw that Jason

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Giambi admitted using steroids to
a grand jury. But steroids are also,

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notwithstanding those kinds
of things, good for you.

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What are some important steroids
in your bodies: testosterone,

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estrogen, glucocorticoids,
all of these things are made

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from cholesterol.
It was a precursor.

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And if you look at the
structure of steroid hormones,

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you recognize that this coupled ring
structure here is very similar to

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what's in them. And
indeed, they're derivatized

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from them. It's also a precursor
for the synthesis of vitamin D.

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And, it is a precursor for
the synthesis of bile acids.

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When your body takes in
triglycerides in your food supply

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and you need to transport fats like
triglycerides across your intestine,

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they need to be emulsified. The way
that triglycerides are emulsified

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are with bile acids. So, you
secrete bile acids into your

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digestive tract. It helps
emulsify fats and helps

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you take them up. So,
cholesterol plays a crucial

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structural role, a
biochemical role with regard to

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hormones, with regard to vitamin D
synthesis, and with regard to bile

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acid synthesis. So,
cholesterol was a good thing,

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all right. Now, if
cholesterol is so

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extraordinarily hydrophobic,
how is it that cholesterol gets

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around the body? It's
almost entirely non-polar.

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It doesn't dissolve in water.
It has one little hydroxyl there.

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It's not going to help a lot. Yep?
Well, the first thing actually is

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it's chemically modified to make
it a little hydrophilic and then it

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does bind to hydrophilic
proteins and particles that help

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get it around. So, the
first thing that happens,

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to be able to, even just to store
cholesterol in any useful form,

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it's not stored as cholesterol
because it's so waxy.

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It would just collapse as a waxy
deposit. What happens is it is

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stored and transported
as cholesterol ester.

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A cholesterol ester,

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or CE, and its esterified by adding
to it, here's my cholesterol again.

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I'll be even
less, there we go.

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This hydroxyl here is used
now for a fatty acid linkage.

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And with this fatty acid
attached to the cholesterol,

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you have a cholesterol ester.
And this is somewhat more soluble.

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All right, where do you
get your cholesterol from?

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Diet. Do we eat cholesterol?
Butter's got cholesterol. What

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else has got cholesterol?
Eggs, a lot of cholesterol.

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So, we eat cholesterol.
So, let's get our sources of

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cholesterol: number one,
diet. And, sources, eggs,

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butter, etc. What
else beyond diet?

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Yeah? Your body actually makes it.
Your own endogenous synthesis. And

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you would imagine that this is
pretty important because cholesterol,

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being half of all plasma membranes,
you can't just count on cholesterol

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being sufficiently
there in your diet.

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So, your body also synthesizes
cholesterol. The synthesis of

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cholesterol is a thing of beauty.
It starts with an incredibly simple

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molecule, acetic acid, right?
And it goes through many

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steps and becomes cholesterol,
which I will summarize here as many

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steps, OK? We'll come
back and talk a moment

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about a few of those steps. But
it's one of these real triumphs

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of biochemistry; the people have
worked out the whole pathway for

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cholesterol biosynthesis. But
it's not, I think, necessary to

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remember all of the steps there.
But it is quite remarkable to go

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from such an extremely simple
molecule like acetic acid all the

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way to cholesterol. And the
fact that people worked all

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this out was a great achievement.
All right, so those are some of the

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things you need.
Then, carrying on here,

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we've got cholesterol coming
in by diet. We're synthesizing

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cholesterol. We're
making cholesterol esters.

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We've got to get them
around the body. So now,

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we're going to take these
cholesterol esters and we're going

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to package them up and send them
off. So, you were saying that proteins

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would be used. Hydrophilic
proteins might be used.

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And indeed, that is the case.
Lipoproteins and lipoprotein

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particles, lipo being fat, of
course, are used to transport

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cholesterol and actually
triglycerins too.

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They are transported in particles
that look roughly like this.

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They have a monolayer of
phospholipids with some protein

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stuck in this monolayer
of phospholipid.

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And, inside is where these
cholesterol esters go.

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So, actually this is where
cholesterols go unesterified.

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So, cholesterol goes in here. In
the cell, we want it esterified.

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When it's in the package,
it's unesterified. So we have a

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monolayer of phospholipids.
We've got some protein stuck in

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that monolayer, and it's
a very little particle.

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Now, these particles
come in different flavors.

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These are very creative
names: low-density lipoprotein

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particles, or LDL. There
are high density lipoprotein

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particles, HDL, and very
low density lipoprotein

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particles, VLDL, and
some other things called

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kilomicrons. Now, you can
imagine that these names

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were assigned based on not so much
information, just based on density,

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right? Somebody was purifying
lipoprotein particles and said,

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well, there are some that
are high density, low density,

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oh, and you just discovered
some very low density ones.

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And this is not a highly
informative description of these

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particles, right? So,
people later worked out that

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these particles were really quite
different, and particularly the

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proteins that are in them, and
those proteins turn out to have

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important addressing roles in
sending these particles to different

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places. The ones that I'll be
interested in today are the LDL

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particles. The LDL particles have
a particular protein in them that is

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called apoprotein
B-100. It doesn't matter,

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but that's the particular targeting
protein there that's in that.

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And these particles are very
large. They are about two and a half

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million Daltons, about
220 angstroms in size,

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and each of them contains
about 1, 00 cholesterols.

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That's a description of
these LDL particles, OK?

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So, cholesterol, if it's
going to be transported in

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the blood, gets packaged up
into LDL particles, and it gets

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sent off to cells. How does
cholesterol get taken up by

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cells from these LDL particles?
How is that cell going to take up

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an LDL particle: a receptor,
right? It stands to reason that

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there's going to be a receptor
that's going to recognize probably

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the protein on the surface of this
thing that'll recognize that and

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internalize this particle. Now,
this stands to reason to us to

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you guys because you guys are
highly sophisticated about all this.

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But how was it that people came to
know this, to find these receptors?

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Well here is a little bit of
an interesting story about how,

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not so long ago, when people didn't
have all the tools in molecular

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biology and all this? And
very few of these cellular

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receptors were known. Two
young medical students began

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studying a fascinating condition.
The young medical students were

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named Joe Goldstein and Mike Brown.
And in fact, at least early in

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their careers they were
working here in Boston. So,

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they studied a fascinating condition
called familial hypercholesterolemia.

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What does hypercholesterolemia
mean? Cholesterol, hyper, a lot of

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cholesterol, emia,
in the blood, right?

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So, a lot of cholesterol in
the blood was this condition.

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And it was characterized, as
you might guess, by the fact that

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patients had a lot of cholesterol in
the blood and that it was familial,

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00:22:58,000 --> 00:23:03,000
meaning what? It
transmitted in families.

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00:23:03,000 --> 00:23:08,000
In fact, it transmitted in
families like a Mendelian trait,

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and it transmitted as an
autosomal co-dominant trait.

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In particular,

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00:23:27,000 --> 00:23:33,000
if we looked at most
individuals in the population,

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00:23:33,000 --> 00:23:38,000
which we'll assume have
genotype plus over plus,

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00:23:38,000 --> 00:23:44,000
and we look at their cholesterol
levels, what we find is maybe they

230
00:23:44,000 --> 00:23:49,000
have 150 mg per desalude.
Now, some people have higher

231
00:23:49,000 --> 00:23:55,000
cholesterols than that, but
I'm going to take that as an

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average. Individuals who,
by virtue of their genetics,

233
00:24:00,000 --> 00:24:06,000
appear to be FH over plus
heterozygotes would have

234
00:24:06,000 --> 00:24:12,000
cholesterols more like
300 mg per desalude,

235
00:24:12,000 --> 00:24:19,000
or about double the normal
level. And, individuals who are FH

236
00:24:19,000 --> 00:24:27,000
homozygotes, FH over FH based on
the pedigree analysis here would have

237
00:24:27,000 --> 00:24:35,000
greater than 600
milligrams per desalude.

238
00:24:35,000 --> 00:24:40,000
In terms of heart attacks, normal
individuals would have heart

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00:24:40,000 --> 00:24:45,000
attacks at the normal age.
That doesn't say anything,

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00:24:45,000 --> 00:24:51,000
does it, because the normal
individuals, the age at which they

241
00:24:51,000 --> 00:24:56,000
have heart attacks is defined
as the normal age. But,

242
00:24:56,000 --> 00:25:01,000
what you will know that's striking
is that individuals who are

243
00:25:01,000 --> 00:25:07,000
heterozygotes would tend to have
heart attacks 10-20 years earlier

244
00:25:07,000 --> 00:25:13,000
than normal age. And,
individuals who are homozygotes

245
00:25:13,000 --> 00:25:19,000
would tend to have heart
attacks below the age of 20.

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00:25:19,000 --> 00:25:26,000
So this might be heart attacks
when you're 60. This might be heart

247
00:25:26,000 --> 00:25:32,000
attacks in your 40s and 50s, and
this might be heart attacks in

248
00:25:32,000 --> 00:25:39,000
your 20s or teens. In
addition, some of these

249
00:25:39,000 --> 00:25:46,000
individuals have very big
cholesterol deposits and things like

250
00:25:46,000 --> 00:25:53,000
that. So, this was a very striking
phenotype: simple Mendelian trait,

251
00:25:53,000 --> 00:26:00,000
autosomal co-dominant, and
to see teenagers or younger,

252
00:26:00,000 --> 00:26:05,000
kids under the age of ten with
massively occluded vessels,

253
00:26:05,000 --> 00:26:10,000
and serious heart disease, and dying
of heart attacks was very striking.

254
00:26:10,000 --> 00:26:15,000
So, Brown and Goldstein decided
that if we wanted to understand

255
00:26:15,000 --> 00:26:20,000
heart disease in the general
population, we should understand

256
00:26:20,000 --> 00:26:26,000
heart disease in patients with
familial hypercholesterolemia,

257
00:26:26,000 --> 00:26:31,000
particularly the homozygotes. Now,
I note that this is about one per

258
00:26:31,000 --> 00:26:35,000
one million individuals. And
you could make a pretty strong

259
00:26:35,000 --> 00:26:39,000
case that Brown and Goldstein are
out of their minds trying to study

260
00:26:39,000 --> 00:26:43,000
familial hypercholesterolemia at
a frequency of one in a million and

261
00:26:43,000 --> 00:26:47,000
try to imagine that that's going to
tell them about heart disease in the

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00:26:47,000 --> 00:26:50,000
general population. All
right, and people made that

263
00:26:50,000 --> 00:26:54,000
case to them and said, what
are you doing? Let's see,

264
00:26:54,000 --> 00:26:58,000
if this is P2, that means
the frequency of the,

265
00:26:58,000 --> 00:27:02,000
Q2, the allele is one in a
thousand in the population, right?

266
00:27:02,000 --> 00:27:05,000
If one in a million people are
homozygotes, the allele is one in 1,

267
00:27:05,000 --> 00:27:09,000
00. And so, the heterozygote
should be about one in 500.

268
00:27:09,000 --> 00:27:13,000
Well, OK, so one in 500's not a
terrible, it's not a small number.

269
00:27:13,000 --> 00:27:17,000
One in 500 people are heterozygotes
for FH. That's maybe a little

270
00:27:17,000 --> 00:27:21,000
better, but still not even a percent.
It's a fifth of a percent of the

271
00:27:21,000 --> 00:27:25,000
population are heterozygotes for FH.
It's still something of a gamble to

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00:27:25,000 --> 00:27:29,000
imagine that by studying this
relatively rare disease we're going

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00:27:29,000 --> 00:27:33,000
to learn about stuff in
the general population.

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00:27:33,000 --> 00:27:36,000
But, Brown and Goldstein
felt strongly that they would.

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00:27:36,000 --> 00:27:39,000
And they did. They wanted to know,
what was the problem with these

276
00:27:39,000 --> 00:27:43,000
individuals? Did they have
problems synthesizing their LDL?

277
00:27:43,000 --> 00:27:46,000
Did they have problems degrading
LDL? Why was there so much LDL

278
00:27:46,000 --> 00:27:50,000
cholesterol in the blood stream?
Maybe they didn't take up the LDL

279
00:27:50,000 --> 00:27:53,000
from the blood stream.
What was wrong? And so,

280
00:27:53,000 --> 00:27:57,000
they studied just
these individuals.

281
00:27:57,000 --> 00:28:02,000
And what they found, to
make an interesting and long

282
00:28:02,000 --> 00:28:07,000
story short was that when they
studied the binding of radioactive

283
00:28:07,000 --> 00:28:13,000
LDL particles to cells from these
patients, they found that the

284
00:28:13,000 --> 00:28:18,000
homozygotes were virtually
unable to take up LDL particles.

285
00:28:18,000 --> 00:28:24,000
There was very low uptake of LDL
particles. They also found that the

286
00:28:24,000 --> 00:28:29,000
heterozygotes had only about half
the normal uptake of LDL particles.

287
00:28:29,000 --> 00:28:35,000
What's your hypothesis about
what the problem is? Sorry?

288
00:28:35,000 --> 00:28:39,000
Well, it's with the uptake, and
what do you think the genetic

289
00:28:39,000 --> 00:28:43,000
basis of this is?
Yep? Well, let's see,

290
00:28:43,000 --> 00:28:47,000
if there's zero in the homozygote,
half the level in the heterozygote,

291
00:28:47,000 --> 00:28:51,000
could be the receptor. And what
could be the problem with receptor?

292
00:28:51,000 --> 00:28:55,000
Mutation of the receptor gene.
What if homozygotes or FH had a

293
00:28:55,000 --> 00:29:00,000
mutation that
abolished the receptor?

294
00:29:00,000 --> 00:29:07,000
OK, that turned out to be the case.
Was the FH was due to mutations in

295
00:29:07,000 --> 00:29:15,000
the LDL receptor on cells?
And indeed, until this point,

296
00:29:15,000 --> 00:29:22,000
the LDL receptor hadn't
been characterized on cells,

297
00:29:22,000 --> 00:29:30,000
but by virtue of Brown and Goldstein
demonstrating that when they did

298
00:29:30,000 --> 00:29:38,000
radioactive labeled
LDL uptake assays,

299
00:29:38,000 --> 00:29:43,000
and they found that FH
homozygotes had no uptake,

300
00:29:43,000 --> 00:29:48,000
virtually no uptake, and that
the heterozygotes had half

301
00:29:48,000 --> 00:29:54,000
the normal level, and that
the wild type individuals,

302
00:29:54,000 --> 00:29:59,000
plus over plus, had the normal level,
they inferred that the gene product

303
00:29:59,000 --> 00:30:05,000
that was mutant in these
individuals encoded the LDL receptor.

304
00:30:05,000 --> 00:30:10,000
And they proceeded to clone this
gene product, and determined that

305
00:30:10,000 --> 00:30:16,000
the gene product encoded a protein
that sat on the cell surface.

306
00:30:16,000 --> 00:30:21,000
It had a cytoplasmic tale.
It had an extracellular tale,

307
00:30:21,000 --> 00:30:27,000
and what it did was it bound
to the apo B-100 protein on

308
00:30:27,000 --> 00:30:34,000
the LDL particle. When it
bound the cell made a little

309
00:30:34,000 --> 00:30:42,000
pit, and in this coded pit, it
came and internalized the LDL

310
00:30:42,000 --> 00:30:50,000
receptor, carrying with it
the LDL particle. And then,

311
00:30:50,000 --> 00:30:58,000
this then went into the cell. The
LDL particle was then degraded,

312
00:30:58,000 --> 00:31:06,000
releasing cholesterol that
could be used by the cell.

313
00:31:06,000 --> 00:31:10,000
And the receptor itself got recycled
back to the surface to work another

314
00:31:10,000 --> 00:31:15,000
day. And this is quite a general
mechanism that is used there by a

315
00:31:15,000 --> 00:31:19,000
lot of trafficking receptors like
this that grab things from the cell

316
00:31:19,000 --> 00:31:24,000
surface, bring them into the cell,
release something into a vesicle,

317
00:31:24,000 --> 00:31:29,000
and then go back onto the surface
there, and that the problem was that

318
00:31:29,000 --> 00:31:34,000
patients FH did not have
functional LDL receptors.

319
00:31:34,000 --> 00:31:39,000
Now, this pointed out, LDL
receptors were very important

320
00:31:39,000 --> 00:31:44,000
here because cells needed to take
up cholesterol from the blood stream,

321
00:31:44,000 --> 00:31:49,000
although they could make
some of their own cholesterol.

322
00:31:49,000 --> 00:31:54,000
But one of the most important
places where cholesterol was

323
00:31:54,000 --> 00:32:00,000
sequestered and taken up from
the blood stream was the liver.

324
00:32:00,000 --> 00:32:09,000
It turns out that the biggest
problem for these patients with

325
00:32:09,000 --> 00:32:18,000
familial hypercholesterolemia was
that the liver is supposed to be

326
00:32:18,000 --> 00:32:27,000
taking up large amounts of LDL to
clear the blood stream and keep the

327
00:32:27,000 --> 00:32:36,000
levels of LDL at the desirable
amount. So, the liver normally is

328
00:32:36,000 --> 00:32:45,000
responsible for taking up clearing
about 75% of LDL from the blood.

329
00:32:45,000 --> 00:32:49,000
If someone has, and other
cells are responsible for

330
00:32:49,000 --> 00:32:53,000
the rest, non-liver cells
take up about 25% of the LDL.

331
00:32:53,000 --> 00:32:57,000
Suppose somebody has half
the level of LDL receptors,

332
00:32:57,000 --> 00:33:01,000
they will take up half as
much of these LDL particles,

333
00:33:01,000 --> 00:33:05,000
and the average level in the
blood would be much higher, about

334
00:33:05,000 --> 00:33:09,000
twofold higher. Suppose
somebody has no LDL

335
00:33:09,000 --> 00:33:12,000
receptors. Well, then the
LDL receptor pathway is not

336
00:33:12,000 --> 00:33:16,000
going to take up these particles,
and they're going to have

337
00:33:16,000 --> 00:33:19,000
outrageously high levels of LDL.
Other mechanisms will kick in and

338
00:33:19,000 --> 00:33:22,000
slightly prevent it from
going to infinity, of course,

339
00:33:22,000 --> 00:33:26,000
because there are other
ways things get cleared out.

340
00:33:26,000 --> 00:33:29,000
But they get huge levels
of LDL because they have no

341
00:33:29,000 --> 00:33:33,000
such receptors. So, this
is the major reason that

342
00:33:33,000 --> 00:33:37,000
there's so much LDL cholesterol
particles in the blood in these

343
00:33:37,000 --> 00:33:42,000
patients who are FH homozygotes.
And then, FH heterozygotes have a

344
00:33:42,000 --> 00:33:47,000
lot. And, well, what are
we going to do about it?

345
00:33:47,000 --> 00:33:51,000
How do you solve a problem like
this? The liver is not doing its

346
00:33:51,000 --> 00:33:56,000
job. Now, I should note, the
liver does one other thing.

347
00:33:56,000 --> 00:34:01,000
the liver not only is the major
source of taking cholesterol,

348
00:34:01,000 --> 00:34:06,000
but it's the major source of
producing LDL cholesterol as well.

349
00:34:06,000 --> 00:34:10,000
The liver produces, I
remember every cell is able to

350
00:34:10,000 --> 00:34:14,000
synthesize cholesterol, but
most of the cholesterol in the

351
00:34:14,000 --> 00:34:18,000
body is synthesized from the
liver and put out. And so,

352
00:34:18,000 --> 00:34:22,000
here we have the liver is
a source of cholesterol,

353
00:34:22,000 --> 00:34:26,000
and it's in this disease not
acting as an appropriate sake for a

354
00:34:26,000 --> 00:34:30,000
cholesterol. It ought to be sucking
up cholesterol and maintaining a

355
00:34:30,000 --> 00:34:34,000
balance of producing cholesterol
and soaking it back up there.

356
00:34:34,000 --> 00:34:39,000
We've got a real problem. Well,
we need to know one more fact,

357
00:34:39,000 --> 00:34:45,000
and then we can solve the disease.
Well, we're not going to solve the

358
00:34:45,000 --> 00:34:50,000
disease, but we'll do
the best we can here. So,

359
00:34:50,000 --> 00:34:56,000
cholesterol synthesis, I
just want to tell you one more

360
00:34:56,000 --> 00:35:02,000
fact about it and then toss you
the problem. Cholesterol synthesis,

361
00:35:02,000 --> 00:35:08,000
I said, was acetate,
acetic acid, goes to stuff,

362
00:35:08,000 --> 00:35:15,000
and let me tell you just
a little bit more about it.

363
00:35:15,000 --> 00:35:21,000
It goes to acetyl CO-A, which
goes to HMG CO-A, which goes

364
00:35:21,000 --> 00:35:28,000
to mevalonate, which goes
on to make cholesterol,

365
00:35:28,000 --> 00:35:35,000
and that the key committed step of
cholesterol synthesis is carried out

366
00:35:35,000 --> 00:35:42,000
by an enzyme called
HMG CO-A reductase, OK?

367
00:35:42,000 --> 00:35:48,000
Now you have all the facts. We
know we've got these particles

368
00:35:48,000 --> 00:35:55,000
that contain cholesterol. We
understand that the liver makes

369
00:35:55,000 --> 00:36:02,000
cholesterol, that you get
cholesterol from your diet.

370
00:36:02,000 --> 00:36:08,000
The liver makes cholesterol.
It takes up cholesterol. We have

371
00:36:08,000 --> 00:36:14,000
some problems with its uptake of
cholesterol. Let's get to work and

372
00:36:14,000 --> 00:36:20,000
design a therapy. How
are we going to do this?

373
00:36:20,000 --> 00:36:27,000
So, we've got patients
designing a rational therapy.

374
00:36:27,000 --> 00:36:45,000
OK, here's your
digestive tract.

375
00:36:45,000 --> 00:36:56,000
You've got some liver here
it's going to take up by

376
00:36:56,000 --> 00:37:06,000
means of diet. It's going
to synthesize cholesterol.

377
00:37:06,000 --> 00:37:15,000
It's going to use cholesterol
to make bile acids.

378
00:37:15,000 --> 00:37:24,000
Those bile acids are going to help
bring back fats because it's going

379
00:37:24,000 --> 00:37:31,000
to emulsify the fats. And so,
the bile acids get recycled.

380
00:37:31,000 --> 00:37:35,000
It's going to put out cholesterol
to the body, and LDL particles are

381
00:37:35,000 --> 00:37:39,000
going to get internalized into
the liver. So, we have our LDLs.

382
00:37:39,000 --> 00:37:43,000
OK, so has everybody got the
action? You take up a cholesterol,

383
00:37:43,000 --> 00:37:48,000
and fats, and things like
that through our diet.

384
00:37:48,000 --> 00:37:52,000
You've got some cholesterol in
our body. We synthesize cholesterol

385
00:37:52,000 --> 00:37:56,000
from acetic acid. We
have this pathway here.

386
00:37:56,000 --> 00:38:01,000
We use cholesterol
to make bile acids.

387
00:38:01,000 --> 00:38:06,000
We take up cholesterol from the
blood stream, and all of these

388
00:38:06,000 --> 00:38:11,000
things together working as a system
control how much cholesterol is in

389
00:38:11,000 --> 00:38:16,000
your body, and most importantly,
how much cholesterol's in your blood

390
00:38:16,000 --> 00:38:21,000
stream in the form of LDL particles.
OK, we have a patient. Maybe it's

391
00:38:21,000 --> 00:38:26,000
a patient with FH homozygosity.
But let's start easier. Let's

392
00:38:26,000 --> 00:38:32,000
start with a patient who's
a heterozygote for FH.

393
00:38:32,000 --> 00:38:45,000
What's our first advice? Eat
well, get plenty of exercise:

394
00:38:45,000 --> 00:38:58,000
this is always good advice.
So, plan one, so strategy number

395
00:38:58,000 --> 00:39:11,000
one: diet, dietary reduction
of cholesterol intake.

396
00:39:11,000 --> 00:39:16,000
Eat less cholesterol.
It's a good bit of advice.

397
00:39:16,000 --> 00:39:21,000
Stop eating eggs, whatever,
you have a serious condition,

398
00:39:21,000 --> 00:39:26,000
don't eat so much better. Does
it do much to reduce LDL levels?

399
00:39:26,000 --> 00:39:31,000
It turns out, not much.
Why doesn't it do much?

400
00:39:31,000 --> 00:39:36,000
What if I reduce dramatically
my intake of cholesterol?

401
00:39:36,000 --> 00:39:40,000
Well, it only makes about a
10% reduction in LDL levels,

402
00:39:40,000 --> 00:39:45,000
which is not enough to get
close to normal. Why? Well,

403
00:39:45,000 --> 00:39:50,000
it turns out your body, number
one, gets more efficient at

404
00:39:50,000 --> 00:39:54,000
taking up cholesterol from your diet.
So, you have some cholesterol there,

405
00:39:54,000 --> 00:39:59,000
and if you're eating less, it
takes up with higher efficiency

406
00:39:59,000 --> 00:40:03,000
the cholesterol that's there.
Your body's good at doing things

407
00:40:03,000 --> 00:40:06,000
like that. It also starts
synthesizing cholesterol.

408
00:40:06,000 --> 00:40:10,000
Don't have enough cholesterol?
We'll make more cholesterol. So,

409
00:40:10,000 --> 00:40:13,000
the liver will make more cholesterol,
put cholesterol out into the blood

410
00:40:13,000 --> 00:40:16,000
stream, and these guys can't take
up the cholesterol with the LDL

411
00:40:16,000 --> 00:40:19,000
receptor as well, and
it clogs it up again.

412
00:40:19,000 --> 00:40:22,000
So in the end, between more
efficient uptake of what is in the

413
00:40:22,000 --> 00:40:26,000
diet and greater synthesis,
we've got to complex the human

414
00:40:26,000 --> 00:40:29,000
system with feedback, and all
you've tried to do is affect

415
00:40:29,000 --> 00:40:34,000
one variable, dietary intake. And
the system regulates so that you

416
00:40:34,000 --> 00:40:41,000
haven't made a very big dent
in the problem. All right,

417
00:40:41,000 --> 00:40:49,000
next strategy, let's try to deplete
some cholesterol from the body.

418
00:40:49,000 --> 00:40:56,000
If we could get some cholesterol
out of the body by some pathway,

419
00:40:56,000 --> 00:41:04,000
we might be able to decrease the
overall levels of cholesterol.

420
00:41:04,000 --> 00:41:08,000
So, where do we have access
to a cholesterol product here?

421
00:41:08,000 --> 00:41:13,000
In the digestive system, we have
bile acids. Got any ideas of what

422
00:41:13,000 --> 00:41:18,000
we could do about the bile acids?
Suppose we could somehow deplete

423
00:41:18,000 --> 00:41:23,000
your bile acids while they're
in your digestive tract.

424
00:41:23,000 --> 00:41:28,000
Then your body would not be
able to recycle those bile acids,

425
00:41:28,000 --> 00:41:33,000
but would have to make more bile
acids. And it would be a sink for

426
00:41:33,000 --> 00:41:38,000
cholesterol, right? It would
start having to use up more

427
00:41:38,000 --> 00:41:42,000
cholesterol to produce enough bile
acids because it would have to use

428
00:41:42,000 --> 00:41:46,000
up more cholesterol. The
liver might have to work harder

429
00:41:46,000 --> 00:41:51,000
to get cholesterol, you know,
synthesizing cholesterol,

430
00:41:51,000 --> 00:41:55,000
but it would also probably up
regulate its LDL receptors to try to

431
00:41:55,000 --> 00:42:00,000
draw in more cholesterol
from the blood stream.

432
00:42:00,000 --> 00:42:04,000
So, this was the clever idea.
Let's try to get ride of bile acids,

433
00:42:04,000 --> 00:42:08,000
or not completely rid of them, but
let's try to complete bile acids.

434
00:42:08,000 --> 00:42:12,000
Therefore, the liver is going
to not be able to reuse them.

435
00:42:12,000 --> 00:42:17,000
It's going to have to make more
bile acids. It's going to need

436
00:42:17,000 --> 00:42:21,000
cholesterol. And so it's going
to up regulate the gene for LDL

437
00:42:21,000 --> 00:42:25,000
receptors and draw in more from the
blood stream. It turns out that you

438
00:42:25,000 --> 00:42:29,000
can feed people bile acid binding
resins. It's perfectly fine.

439
00:42:29,000 --> 00:42:34,000
Just eat them, and you can give
people bile acid binding resins.

440
00:42:34,000 --> 00:42:41,000
So, strategy number two, and
what they will do is then they

441
00:42:41,000 --> 00:42:49,000
will, in their feces, eliminate
some fraction of the bile

442
00:42:49,000 --> 00:42:56,000
acids and as a result they will
be able to get rid of some of their

443
00:42:56,000 --> 00:43:04,000
cholesterol, and they will be
able to decrease their overall

444
00:43:04,000 --> 00:43:14,000
cholesterol levels.
Does this work?

445
00:43:14,000 --> 00:43:28,000
It does, and you can get
maybe a 20-25% reduction. But

446
00:43:28,000 --> 00:43:37,000
what's the problem? You can't
completely get rid of them,

447
00:43:37,000 --> 00:43:41,000
right, because they're necessary.
So, we'll be able to get rid of

448
00:43:41,000 --> 00:43:46,000
some bile acids. That's
really the problem is,

449
00:43:46,000 --> 00:43:50,000
see, we're sitting here saying so
cleverly we're going to feed the

450
00:43:50,000 --> 00:43:55,000
body less cholesterol. We're
going to draw cholesterol out

451
00:43:55,000 --> 00:43:59,000
of the body by removing bile acids,
and force the liver to take up more

452
00:43:59,000 --> 00:44:04,000
cholesterol from the
blood stream, right?

453
00:44:04,000 --> 00:44:07,000
And hopefully it'll help regulate
the gene. And it does help regulate

454
00:44:07,000 --> 00:44:10,000
the gene. When starved for
cholesterol, cells up regulate their

455
00:44:10,000 --> 00:44:13,000
LDL receptor gene and make
more LDL receptors. That works.

456
00:44:13,000 --> 00:44:16,000
But we've forgotten one aspect of
the system, and that was the liver

457
00:44:16,000 --> 00:44:19,000
has another option, which
was synthesize its own

458
00:44:19,000 --> 00:44:22,000
cholesterol. So, we've
got a complex system with

459
00:44:22,000 --> 00:44:25,000
multiple feedbacks. We've
affected it at the level of

460
00:44:25,000 --> 00:44:28,000
diet. We've affected at the
level here of drawing stuff out.

461
00:44:28,000 --> 00:44:32,000
We've managed to get some up
regulation the LDL receptor gene.

462
00:44:32,000 --> 00:44:38,000
But it's not enough because the
liver's choosing to make more

463
00:44:38,000 --> 00:44:45,000
cholesterol through its
endogenous synthesis pathway.

464
00:44:45,000 --> 00:44:51,000
So, let's keep going.
What do you recommend?

465
00:44:51,000 --> 00:44:58,000
Yes? Ooh, ooh, I like that. What
do you think will happen then?

466
00:44:58,000 --> 00:45:02,000
So, I won't make as much cholesterol.
What's the liver going to have to

467
00:45:02,000 --> 00:45:06,000
do then? And it will up regulate
its LDL receptors to do that,

468
00:45:06,000 --> 00:45:10,000
take up more cholesterol
from the blood stream. So now,

469
00:45:10,000 --> 00:45:14,000
we back the liver into a corner,
right? It needs more cholesterol.

470
00:45:14,000 --> 00:45:18,000
We're going to inhibit the
synthesis of cholesterol,

471
00:45:18,000 --> 00:45:22,000
and therefore it's going
to go to its second source,

472
00:45:22,000 --> 00:45:26,000
which is uptake from the blood,
and it's going to induce more LDL

473
00:45:26,000 --> 00:45:30,000
reception. Everybody got
your plan? So, let's see.

474
00:45:30,000 --> 00:45:36,000
Strategy would be inhibit
cholesterol synthesis.

475
00:45:36,000 --> 00:45:42,000
This is in addition also
inhibit cholesterol synthesis.

476
00:45:42,000 --> 00:45:48,000
And, you wanted to inhibit one
of those steps. Any preference of

477
00:45:48,000 --> 00:45:54,000
where you'd like to inhibit the step?
How about the first committed step

478
00:45:54,000 --> 00:46:00,000
of cholesterol synthesis?
So, how about H, M, G, CO-A

479
00:46:00,000 --> 00:46:15,000
reductase inhibitors?

480
00:46:15,000 --> 00:46:19,000
Well, it turns out that people
found HMG CO-A reductase inhibitors.

481
00:46:19,000 --> 00:46:23,000
Lovastatin, a fungal product
inhibits HMG CO-A reductase.

482
00:46:23,000 --> 00:46:27,000
And then, companies, Merck
and then many other companies,

483
00:46:27,000 --> 00:46:31,000
developed all sorts of what
are called statin drugs that

484
00:46:31,000 --> 00:46:35,000
inhibit that enzyme. I would
venture to say that a large

485
00:46:35,000 --> 00:46:39,000
fraction of your parents take
statin drugs to lower cholesterol.

486
00:46:39,000 --> 00:46:44,000
And this is how it works. It
inhibits the endogenous synthesis

487
00:46:44,000 --> 00:46:48,000
pathway at the step
HMG CO-A reductase. And,

488
00:46:48,000 --> 00:46:53,000
in addition, if they do things
like take bile acid binding resins,

489
00:46:53,000 --> 00:46:58,000
and there's some combinations of
those things, and also controlled

490
00:46:58,000 --> 00:47:02,000
your dietary intake of cholesterol,
and FH heterozygote can get a 60%

491
00:47:02,000 --> 00:47:07,000
reduction in LDL particle
loss. That is mighty good.

492
00:47:07,000 --> 00:47:12,000
That brings them down to normal.
Yeah? Yeah? Yep. So we're not

493
00:47:12,000 --> 00:47:17,000
talking about totally removing it.
We're talking about decreasing it.

494
00:47:17,000 --> 00:47:22,000
We're bringing it back down
to a normal level. Well,

495
00:47:22,000 --> 00:47:27,000
it turns out that the cells out
there will up regulate their LDL

496
00:47:27,000 --> 00:47:33,000
receptors as well, and I
haven't focused on that.

497
00:47:33,000 --> 00:47:36,000
But they're taking care of
themselves. It turns out,

498
00:47:36,000 --> 00:47:39,000
you have to worry about all these
strategies. This is too clever by

499
00:47:39,000 --> 00:47:42,000
half because you're going to
mess up things in the periphery.

500
00:47:42,000 --> 00:47:45,000
But it turns out the peripheral
cells take care of themselves.

501
00:47:45,000 --> 00:47:49,000
They'll up regulate their LDL
receptors enough to get things in.

502
00:47:49,000 --> 00:47:52,000
And the big problem is that
the liver's not doing its job.

503
00:47:52,000 --> 00:47:55,000
But you have to do the clinical
tests to see that that's the case.

504
00:47:55,000 --> 00:47:58,000
This turns out to be a
strategy for FH heterozygotes.

505
00:47:58,000 --> 00:48:02,000
But I just said that many of
your parents take these drugs.

506
00:48:02,000 --> 00:48:05,000
Most of your parents
aren't FH heterozygotes.

507
00:48:05,000 --> 00:48:09,000
Perhaps none of your
parents are FH heterozygotes.

508
00:48:09,000 --> 00:48:12,000
That turned out to be one of the
most remarkable outcomes of studying

509
00:48:12,000 --> 00:48:16,000
this rare genetic disease.
Well, as it turned out, this

510
00:48:16,000 --> 00:48:19,000
strategy, which had been the
understanding that had been

511
00:48:19,000 --> 00:48:23,000
developed from this exceedingly
rare genetic disease,

512
00:48:23,000 --> 00:48:26,000
and the strategy that had been
developed with an eye towards these

513
00:48:26,000 --> 00:48:30,000
FH heterozygotes turns out to also
work in normal individuals with high

514
00:48:30,000 --> 00:48:33,000
cholesterol not because of a
complete mutation in the LDL

515
00:48:33,000 --> 00:48:37,000
receptor, but because of,
perhaps, other differences,

516
00:48:37,000 --> 00:48:40,000
genetic differences that are weaker.
And in fact, tens of millions of

517
00:48:40,000 --> 00:48:44,000
people take these therapies that
were developed for this very rare

518
00:48:44,000 --> 00:48:47,000
situation. This is a perfect
example of where understanding a

519
00:48:47,000 --> 00:48:51,000
rare genetic disease points us
to the basis for a physiological

520
00:48:51,000 --> 00:48:54,000
pathway, in particular, all
these feedback loops that allow

521
00:48:54,000 --> 00:48:58,000
us to do something that
helps everybody. So,

522
00:48:58,000 --> 00:49:02,000
this has become a
major, major therapy.

523
00:49:02,000 --> 00:49:06,000
Who were the only people who don't
benefit from this particular therapy

524
00:49:06,000 --> 00:49:10,000
of tricking the body into up
regulating the LDL receptors?

525
00:49:10,000 --> 00:49:15,000
Homozygotes, because they don't
have a gene to be up regulated.

526
00:49:15,000 --> 00:49:19,000
They don't have a functional
gene to be up regulated.

527
00:49:19,000 --> 00:49:24,000
And so, homozygotes need
something else. What do they need?

528
00:49:24,000 --> 00:49:28,000
Gene therapy. The best idea that
people have here since the liver

529
00:49:28,000 --> 00:49:33,000
regenerates tremendously would be
able to take out some liver cells,

530
00:49:33,000 --> 00:49:37,000
add back genes for LDL receptors,
and repopulate a liver with LDL

531
00:49:37,000 --> 00:49:42,000
receptor transgenic cells.
And that would help them.

532
00:49:42,000 --> 00:49:46,000
Anyway, this is meant to illustrate
the power of rational therapy,

533
00:49:46,000 --> 00:49:51,000
that understanding things, can you
imagine trying to do this by hit or

534
00:49:51,000 --> 00:49:55,000
miss? It was your design knowing
the pieces that God is here,

535
00:49:55,000 --> 00:50:00,000
and this is basically what we're
trying to do with all of medicine is

536
00:50:00,000 --> 00:50:04,000
get to the point where we can
design things that really do work.

537
00:50:04,000 --> 00:50:09,000
See you
next time.