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JOANNE STUBBE: Where we were at at the end of the last lecture

was trying to figure out what do we

do with the fact that cholesterol--

its solubility is five micromolar.

Yet if you look inside your blood,

the levels would be 5 millimolar.

And so the question is, how does it gets transported?

And it gets transported in a complex fashion.

We need to deal with that with any kind of very

insoluble lipophilic materials.

And I briefly introduced you to lipoproteins,

which are mixtures of different kinds of lipids,

triacylglycerols, phospholipids, cholesterol,

cholesterol esters.

And the key question we learned in the first couple

lectures that cholesterol could be biosynthesized.

And what we started focusing on in the last lecture

was that it can be taken up by the diet.

That's what we're focusing on now.

And then after we do a little more background,

then how is it taken up and then how is this all regulated?

How do you control biosynthesis versus cholesterol

from the diet.

What are the sort of major mechanisms?

So at the end of the last lecture

I'd given you a second picture.

And the PowerPoint-- the original PowerPoint

didn't have this figure.

This is taken out of a new Voet and Voet--

the newest Voet and Voet-- which I think better

describes what's going on.

But really sort of what you need to know

is you form these particles, chylomicrons,

if you look at the handout I gave

you have lots of proteins, all kinds of lipids, cholesterol.

And they get into the bloodstream

and they pass off as they go through adipocytes

or as they go through muscle.

The surface of these cells have lipases, phospholipases

that can clip off the fatty acids

that you need for metabolism at most cells.

And what happens is the size of these particles just change.

And so in the end, you remove the triacylglycerols

and you remove phospholipids.

And what you're left with is more of a cholesterol.

And that-- and so what happens is the chylomicrons change

size.

They call them the remnants.

And there are receptors on liver cells, which

can take up these remnants, these lipoprotein remnants.

And then they repackage them into other lipoproteins.

And again, the differences in the lipoproteins

we talked about very briefly, we have an outline.

Somebody measured these with a--

again, they're variable, but they're based on density.

And so the liver repackages these things

to a particle that's very low density, lipoprotein.

And then again, they can dump off components

into the tissues where you can use the lipids to do

metabolism, changing the size, intermediate density,

eventually low density lipoprotein which

is what we're focused on now.

And then today what we're focused

on is how does the low density lipoprotein get taken up

by the liver?

And also, can it get taken up by other kinds of cells?

And if you have excess cholesterol produced

in any of these extrahepatic cells,

it can be taken up to form particles called high density

lipoproteins.

And they can come back.

So they act as cholesterol scavengers,

come back and deliver it back into the liver

by a mechanism that is really different from what we're going

to be talking about today.

So that's the overview picture.

And so what I want to do now is focus

on the question, why do we care about cholesterol

and what was the motivator for Brown

and Goldstein's discovery of the low density lipoprotein

receptor.

So this is the motivator.

They were seeing when they were at medical school,

a number of children that presented at an early age.

These guys were six and eight.

And the way they present, if they turn out

to have both genes, both copies of the gene

are messed up for low density lipoprotein

receptor, that's called familial hypercholesterolemia.

The way they present is they have these little xanthomases

that are apparently yellow.

And what they are is they're full of cholesterol.

OK, and so if you have someone that's heterozygous

rather than homozygous--

these guys are homozygous--

you still see these but you see it

at a much later time in their life.

And so again, what it is, it's a function of the fact

that you have too much cholesterol

and this is the way--

one of the ways-- it manifests itself.

The second way it manifests itself

is if you look at the concentration of low density

lipoprotein and the plasma, which

is given in milligrams for 100 mils, what you see

is the concentrations of cholesterol

are actually 5 to 10 times higher.

So that's the manifestation.

And children that manifest at this early age

die of heart attacks by the time they're 30.

And so this was the motivator.

They were trying to figure out what is the basis

or bases for this disease.

So that's what I said.

This is a dominant effect.

At the time, the gene or genes responsible for this

were not known.

It turns out from the data that I've gotten from some paper,

one in 500 people are heterozygotes.

That's quite prevalent, actually.

But the ones that manifest themselves

in this really terrible way early on

is something like one in a million.

And so-- but even the heterozygotes,

Brown and Goldstein study all of these people,

also manifest in this way.

They have elevated cholesterol levels.

And so this was is a huge problem.

And so they decided they wanted to really devote

their life to it.

And I think they didn't know this in the beginning,

but it's really associated with one gene.

Most diseases are much more complicated than that.

And so I think because of the, quote, "simplicity" unquote,

you'll see it's not so simple, they

were able to make progress.

And these experiments were carried out really

sort of in the--

started in the 1970s.

So I think Brown and Goldstein-- we talked about the cholesterol

biosynthetic pathway.

And we talked about what was rate limiting.

So hopefully you all know that the rate limiting step

is the reduction of hydroxymethylglutaryl CoA down.

So the CoA is reduced all the way down to an alcohol

and that product is mevalonic acid.

And if you can't remember this, you

should pull out the biosynthetic pathway.

And that was proposed to be by other people working

in this field to be the rate limiting

step in this overall process.

And when you take an introductory course

in biochemistry, you talk about regulation.

I guess it depends on who's teaching it,

how much you talk about regulation.

But of course, one of the major mechanisms of regulation

that's sort of easy to understand in some fashion,

is that oftentimes the end product of a pathway

can come back way at the beginning

and inhibit the pathway.

So that's called feedback inhibition.

We saw that cholesterol biosynthesis was 30 steps.

And if you go back and you look at the pathway, you know,

I think this is step four or five.

I can't remember which one it is.

And so the model was--