- [Instructor] Now the ultimate goal in fat metabolism
is to be able to deliver some triacylglycerides,
which I'm gonna abbreviate here at TAG,
which remember is the chemical name for a fat molecule,
or free fatty acids,
which I'll abbreviate here at FFA,
which if you recall are the kind of monomer subunits
of these fat molecules directly into the bloodstream
where they can eventually reach capillary beds
like the one that I've drawn here.
So I'll go ahead and label this as a capillary bed,
and it's important that they reach these capillary beds
because it's at this point where they can diffuse
to surrounding tissues such as muscle or heart tissue,
for example, where they can be taken up by these tissues
and oxidized to obtain cellular energy in the form of ATP.
Now I want to remind you that there are
three main sources of these triacylglycerides
or free fatty acids that can enter the bloodstream,
and so I'm gonna go ahead and scroll up here
and show you kind of what I've already drawn out here
and go ahead and explain it.
Starting off here on the far left
I've drawn a cheeseburger,
perhaps not the best drawing in the world,
but just to remind us that one of our sources of fat
that ultimately reaches our bloodstream
is directly from our diet.
So recall that our small intestine
digests our food and packages the fat molecules,
the triacylglycerides,
into protein carrier molecules called chylomicrons,
which travel through the lymphatic circulation
but eventually empty into our bloodstream
where they can enter capillary beds.
Now the second way that we can get
some fat into our bloodstream
is directly from adipose cells.
So recall that adipose cells
are specialized cells inside of our body
that can store large amounts of fat,
and so that's kind of what I've drawn here
in these yellow circles within these cells,
these large fatty droplets.
And several hours after a meal,
when your hormone insulin begins to drop inside of your body
and other hormones such as glucagon begin to rise,
they signal these adipose cells
to release free fatty acids
directly into the bloodstream,
and recall that free fatty acids are very hydrophobic,
so they kind of surf,
essentially they kind of attach themselves
onto albumin molecules,
which is a special type of protein
that's always found inside of our bloodstream.
Now the third way that we can get some fat
into our bloodstream is by synthesizing it
directly inside of the liver,
which I've kind of drawn an outline of here.
Now the liver cells are especially equipped
with the right type and number of enzymes
to be able to convert excess glucose,
that is the glucose that's not being used
for ATP synthesis or glycogen synthesis,
into fatty acids.
Then, like the small intestine,
the liver essentially packages these fatty acids
into triacylglyceride molecules
and packages them together with cholesterol,
another hydrophobic molecule,
into another specialized protein carrier molecule
like chylomicrons, but this one
has a slightly different name.
It's called very low density lipoprotein,
or VLDL for short.
And this of course is sent off to the bloodstream,
where it will eventually reach capillary beds
and be taken up by surrounding tissues,
even perhaps adipose cells,
which might store it up for later use.
So now that we've gone over this overview,
I want to zoom in on one of these steps.
I want to zoom in on this step here,
going from glucose to fatty acids inside of the liver,
which is commonly referred to
simply as fatty acid synthesis.
And to do this,
I want to go ahead and kind of just zoom in
on one single cell inside of the liver
to visualize what's going on at the cellular level
to be able to allow us to convert glucose into a fatty acid.
And so I'm gonna go ahead and scroll the screen here
so we can have some more room.
All right, so I'm gonna quickly draw
an outline of a representative cell,
and then we'll go ahead and quickly label
some important compartments that we want to talk about.
So the first one is simply the cytoplasm,
and there's a lot going on in the cytoplasm.
But we also need to talk about
what's going on in another organelle inside the cell,
and that organelle is the mitochondria,
and I'm gonna go ahead and draw the kind of two membranes
that it has here.
We're not gonna talk about this too much,
but just because it is important to remember
that this has an inner membrane and an outer membrane.
Remember that the electron transport chain
is of course located on the inner membrane,
and the mitochondria is also within it.
It's the site of the Krebs cycle,
which continues, notably,
to break down glucose following glycolysis,
which takes place inside of the cytoplasm.
Now since we ultimately want to get down
to how extra glucose can be eventually
converted into fatty acids,
we need to actually make sure and remind ourselves
how the breakdown of glucose proceeds.
So as a very, very quick review,
recall that glucose enters our cells from the bloodstream
and it enters the metabolic pathway called glycolysis,
which takes place inside the cytoplasm.
And the end product of glycolysis is pyruvate,
and I'll also remind you
that for every one molecule of glucose,
which is a six-carbon molecule,
so one, two, three, four, five, six,
we form two molecules of pyruvate,
which is a three-carbon compound.
Subsequently, pyruvate is actively transported
across the mitochondrial membrane
by specialized carrier proteins located on the membrane,
and once pyruvate reaches the inside of the mitochondria,
also known as the inner mitochondrial matrix,
there is a enzyme that's only found
in the mitochondria called pyruvate dehydrogenase,
often abbreviated as PDH,
which oxidizes and removes one carbon from pyruvate.
So remember, we had three carbons,
and now it turns it into a two-carbon molecule
called acetyl-CoA.
Now you might recall that this two-carbon structure
is not done being broken down or oxidized.
There's still some energy that we can extract
from this two-carbon molecule,
and it's extracted inside of the Krebs cycle.
So remember that there are many, many intermediates
along the Krebs cycle,
but I only want to mention a couple
that will be relevant when we talk about
how this breakdown of glucose
converges with the synthesis of fatty acids.
So remember first off that a four-carbon molecule
called oxaloacetoacetate,
which I'm abbreviating here as OAA,
combines with one molecule of acetyl-CoA
to produce a sixth carbon molecule now called citrate.
And citrate continues to be modified,
oxidized, and even broken down a little bit more,
and it returns to form oxaloacetate,
which means that we lose two carbons
somewhere along this cycle,
which we do indeed.
We lose these as two molecules of carbon dioxide,
so those two carbons of acetyl-CoA exit as carbon dioxide,
and we also form a number of reduced
electron carrier molecules called NADH and FADH2,
which shuttle their electrons from the oxidation process
that occurs in the Krebs cycle
to the electron transport chain,
which is located on this inner mitochondrial membrane.
How convenient, right?
And then from there,
we can produce ATP using oxidated phosphorylation.
All right, so after that quick whirlwind tour
of the breakdown of glucose,
you might be wondering where do we convert
glucose into fatty acids?
And it turns out that one of the intermediates
of the breakdown of glucose,
which is acetyl-CoA, this two carbon molecule
located in the mitochondrial inner matrix,
is a precursor for fatty acid synthesis,
and we're gonna go through all of the steps,
but just to take a step back for a moment,
the big picture way that I kind of like to think about this
is that remember that fatty acids,
I'm gonna go ahead and draw off to the side here,
remember that most of it
is just a repeating carbon hydrogen backbone
shown here in this kind of line stick model here.
And so in that sense,
really we want to basically be able
to link together carbon-carbon bonds,
and this acetyl-CoA is just a pair of carbon-carbon bonds
that we can ultimately link together.
Now it turns out that we have an interesting situation
when it comes to fatty acid synthesis
and linking all of these acetyl-CoA molecules together,
which is that all of the enzymes necessary
for fatty acid synthesis,
I'm gonna say enzymes for fatty acid synthesis,
are located in the cytoplasm.
And that's a bit problematic,
because remember our acetyl-CoA molecule
is in the mitochondria.
Now your first thought might be,
well, pyruvate was able to shuttle across
using some protein career molecules in these membranes
into the mitochondria.
Why can't acetyl-CoA do the same
going the opposite direction?
Unfortunately, for some reason or the other,
our body has evolved not to have any means
to be able to transport this through
its mitochondrial membrane.
There are no protein transporters or carrier molecules
like we had for pyruvate to be able to
essentially shuttle acetyl-CoA in either direction
across this mitochondrial membrane.
But notably, our body does have a protein shuttle
across this mitochondrial membrane for the molecule citrate,
and remember that citrate contains acetyl-CoA.
Of course, it also contains this molecule acetylacetate
that combines with it.
And so let's see what happens
when this shuttles across the mitochondrial membrane.
Now once citrate reaches the cytoplasm,
it turns out that there is an enzyme
within the cytoplasm that is able to
break citrate up back into oxaloacetate,
as well as the molecule that we're interested in,
which is of course acetyl-CoA.
Now when I first learned about this,
it kind of struck me as a really roundabout way
to kind of accomplish what seems
like a pretty simple task, right,
which is to get acetyl-CoA into the cytoplasm
where the enzymes or fatty acid synthesis
can link it together to form a fatty acid.
But it turns out that there might be a benefit
for this citrate shuttle to make fatty acid synthesis
perhaps more efficient,
and so I want to briefly talk about that,
but I want to erase this just to give us some more room.
Now it turns out that this four-carbon molecule,
oxaloacetate, is not going to be used
for fatty acid synthesis.
And so naturally our body says why don't we recycle it?
And in fact, we do have some enzymes
that can convert it back to this molecule pyruvate,
and notice that pyruvate can essentially,
once it goes back to the mitochondria,
it'll be turned into acetyl-CoA
and this entire cycle can continue.
Now although we're not gonna go over
the detailed mechanism by which oxaloacetate
is converted to pyruvate,
what is important, kind of a big picture idea to note here,
is that we're going from a four-carbon
to three-carbon molecule,
and so we're gonna lose a carbon, actually,
as carbon dioxide during this process.
And simultaneous with this step,
we're actually oxidizing that particular intermediate.
And so when we oxidize something,
we're able to reduce something else,
and it turns out that what we reduce in this case
is a molecule of NAD+.
And so it's reduced to NADPH,
and you may recall that you've seen NADPH also
as a product of the pentose phosphate pathway,
and of course we normally think about
the pentose phosphate pathway as being the major pathway
for the production of NADPH,
but this step also allows us to produce
a molecule of NADPH as well.
Now one of the uses of NADPH that you might recall
is that because it's associated with these electrons,
it can serve as a source of reducing power
to help with anabolic reactions.
And remember that anabolic reactions
are anything that involve building up a molecule,
including fatty acid synthesis,
which is exactly what we're trying to accomplish here.
So to summarize and just kind of tie up
everything that we've just talked about here,
we've been able to get acetyl-CoA into the cytoplasm
where all of the enzymes necessary
for fatty acid synthesis are located.
And this is important because we're gonna use acetyl-CoA,
multiple acetyl-CoA, kind of a precursor molecule,
so to say, to build up a fatty acid.
And of course because this is an anabolic reaction,
we're going to need some ATP somewhere along the way,
and we're also going to need some reducing power
to kind of help form all of those carbon-carbon bonds,
and we can get that using NADPH.
Of course, NADPH can be supplied
by the pentose phosphate pathway,
but conveniently, perhaps,
by using this citrate shuttle,
we're also able to produce a molecule of NADPH
from the conversion of oxaloacetate into pyruvate.
In the next video,
we'll pick up right here in the cytoplasm
to talk about how this conversion
from acetyl-CoA into a fatty acid occurs.