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PROFESSOR: We're now at storyboard 23.
Let's look at panel A. Our last metabolism
topic under the general umbrella of catabolism is ketone bodies.
Ketone bodies are only covered in two pages in the book,
but they're medically very important.
The medical relevance of ketone bodies
stems from their role in starvation
and their role in diabetes.
Let's look at panel A. This panel shows various sources of
and uses of acetyl CoA.
It shows that ketone bodies are made from Acetyl coenzyme A.
So let's start this part of the lecture
with a discussion of where acetyl CoA comes from,
and what its various states are including
the formation of ketone bodies.
We just finished talking about fatty acid catabolism.
So let's start on the right of this figure.
We see that a fatty acid can be broken down
to form acetyl CoA by beta oxidation,
usually with the objective of generating energy.
If we follow the acetyl CoA from beta oxidation
down into the TCA cycle, we see that it
will be fully oxidized to carbon dioxide with the generation
of a lot of energy that can be used
for mechanical work, biosynthesis, and other things.
A second source of Acetyl CoA can
be seen to the left, where we see
glycogen breakdown to glucose or glucose
can be directly imported into a cell.
In either case, the glucose that we take in or liberate
from its storage depot, glycogen,
can be converted into acetyl coenzyme A.
Glycerol can be generated from the backbone
of a metabolized triacylglyceride.
It enters glycolysis as dihydroxyacetone phosphate
and then can progress to acetyl CoA by way of glycolysis.
Alanine can transiminate into pyruvate,
which is converted subsequently to acetyl CoA
by pyruvate dehydrogenase.
This diagram shows us that many pathways converge
to generate acetyl coenzyme A. Carbohydrates, amino acids,
fatty acids, all can act as a source
of this important precursor to energy.
Aside from being processed by the TCA cycle, on the left,
we see a broken line pathway involving
fatty acid biosynthesis.
This is going to be the next topic we come to
after this discussion of ketone body formation.
The pathway on the right with the broken lines
is the pathway leading to ketone bodies
which is called ketogenesis.
In the box at the top of panel A is a cartoon reminding me
to tell you that acetyl CoA cannot escape from the cell.
Moreover, it cannot even easily escape from the mitochondrion.
In order for acetyl CoA to leave the cell
and be transported from one organ to another,
it needs to be converted into ketone bodies.
Another way to look at ketone bodies
is that these are mobile or portable forms
of Acetyl CoA that can go from a source organ, which is usually
the liver, to a target organ, which may need them in order
to generate energy by way of the TCA cycle.
The target organ for example could be brain
under conditions of starvation, or it
could be skeletal muscle if you have
to run away from something.
Let's look at panel B. There are five key facts that we need
to know about ketone bodies.
First, Ketogenesis mainly occurs in the liver.
The liver manufactures ketone bodies
and then exports them to other organs for use.
These reactions typically happen when the levels of oxaloacetate
become limiting in their mitochondrion.
And I'll give you an example of why
this is the case when I talk about starvation a little later
in this lecture.
The second important fact is that these
are the primary metabolic fuels of the heart and skeletal
muscle under normal conditions.
The third fact is that ketone bodies
become the major metabolic fuel of all cells
under conditions of starvation, even
cells of the brain after a few days of starvation
will convert from glucose being the preferred metabolic fuel
to accepting ketone bodies as their major source of energy.
The fourth fact I want to talk about with regard
to ketone bodies is that they are
produced in excess in diabetes.
I'll talk a little bit more about that
later in the lecture.
Finally, ketogenesis occurs in the mitochondrion, primarily
the mitochondrion of the liver.
So these are mitochondrial reactions.
Panel C shows the three classical ketone bodies,
acetoacetate, beta hydroxybutyrate, and acetone.
From the standpoint of chemical accuracy,
it's obvious that beta hydroxybutyrate
is an alcohol and not a ketone.
Nevertheless, it's lumped in with the ketone bodies
for historical reasons.
Acetoacetate and beta hydroxybutyrate
are what I'll call quote unquote "useful" ketone
bodies from the standpoint of serving as precursors
to metabolic energy.
Acetone by contrast, is not useful by this criterion.
Acetone however, is a useful biomarker,
because sometimes its presence can help diagnose diabetes.
On a personal note, I come from a long line of diabetics.
I remember when I was a little kid, my dad before he
was diagnosed, would come home from work
at the end of the day.
He had very poor circulation.
So my two sisters and I would try
to rub his legs to give him a kind of massage
to make his circulation a little bit better.
I remember very clearly my older sister saying, "gee,
dad smells like mom's nail polish remover,"
and that's because he was a diabetic producing
acetone, which was used at the time at least
as nail polish remover.
We had no idea at the time what was going on.
A few months later, my dad was diagnosed as a type 2 diabetic.
I now know that the fruity odor we smelled on his breath
was acetone.
As I said, acetone is a biomarker of this disease.
One last point with regard to the story board.
Note that the acetoacetate and beta hydroxybutyrate molecules
are acids.
In diabetics, these acids can be produced
as we'll see later in sufficiently
high concentrations to lower the pH of the blood
quite substantially.
Keep in mind that lowering the pH
is the same thing as increasing the concentration of protons
in the blood.
These concentrated protons will have physiological relevance
that I'll discuss later.
When a diabetic enters the phase where the pH of their blood
is dangerously low, that's called diabetic acidosis.
Let's now turn to Panel D. At this point
I want to describe the detailed biochemical reactions that
give rise to ketone bodies.
To make a ketone body we're going
to need three molecules of acetyl coenzyme
A. One of these molecules is going to be catalytic.
That is, it's going to be restored at the overall end
of the process of ketogenesis.
Let's start by imagining a scenario
in the mitochondrion of a liver cell
where oxaloacetate becomes limiting.
I'll talk about physiological states under which oxaloacetate
becomes limiting or sparse a little bit later.
Acetyl CoA cannot enter the TCA cycle,
because citrate synthase lacks oxaloacetate as a reaction
partner.
The concentration of acetyl CoA starts to accumulate.
Then the beta ketothiolase reaction
that is the last step in fatty acid bio oxidation
reverses owing to the high concentration of product acetyl
CoA.
So two acetyl CoAs come together in order
to form acetoacetyl coenzyme A. Note
that I put markers on each of the carbons
of the acetoacetyl coenzyme A. A third acetoacetyl coenzyme
A is then added to the gamma carbon
of the acetoacetyl coenzyme A. That's the carbon that
has the filled-in square.
The enzyme that catalyzed this last reaction
is HMG Coenzyme A reductase, where HMG stands
for hydroxymethylglutaryl.
HMG CoA is a six-carbon branch chain molecule.
In the present situation, we're going
to look at HMG CoA as the source of ketone bodies
in the mitochondrion, but I want you
to keep in mind that if this reaction were
to occur not in the mitochondrion
but in the cytoplasm, the resulting HMG CoA could
be used for other pathways.
For example, HMG CoA in the cytosol
is the precursor to cholesterol.
With that in mind, let's return our attention
to the mitochondrion and ketogenesis.
The mitochondrial enzyme HMG CoA lyase
will split the HMG CoA, knocking off
an acetyl CoA in liberating as the final product
acetoacetate, which is our first of three ketone bodies.
Acetoacetate is a beta keto acid and hence,
prone to spontaneous decarboxylation.
Non enzymatically, this will happen at some slow rate
in order to liberate CO2 and produce acetone, which
is our second ketone body.
This acetone gives the fruity smell
to the breath of a diabetic whose disease is out
of control.
Acetone is not going to be biochemically useful to us,
for example it's not going to be metabolized to generate energy.
The second chemical fate of the acetoacetate
is its reduction by NADH using the enzyme beta hydroxybutyrate
dehydrogenase.
This reduction forms our third ketone body beta
hydroxybutyrate, which is a biochemically useful molecule
in that it serves as a good metabolic fuel.
Acetoacetate and beta hydroxybutyrate
do not need any kind of special transporter
to get out of the cell into the blood.
They diffuse through the mitochondrial membrane
and later through the cell membrane.
They are then transported by the circulatory system
from the liver to organs that need them for energy.
As you mentioned above, ketone bodies
are portable forms of acetyl CoA.
In a real sense, the liver by making these ketone bodies
is acting as a food caterer where
ketone bodies represent food that's
delivered to other organs.
At this point let's look at storyboard 24
panel A. Now let's take a look what
happens when the ketone bodies travel by the blood
and are taken up by another organ such as muscle.
Acetoacetate, which I'll refer to as ketone body
one is good to go and is ready to enter
the main stream of metabolism.
So I'm going to come back to it in a minute.
The beta hydroxybutyrate, by contrast,
has to be processed in order for it
to be useful to the target organ skeletal muscle in this case.
In step two, the muscle form of beta hydroxybutyrate
dehydrogenase will use NAD plus to oxidize
the beta hydroxybutyrate into acetoacetate, which
joins the pool of acetoacetate that came in directly
from the blood.
We now have to put a thioester group on the acetoacetate,
and that comes from an unusual source.
In step three you'll see a succinyl coenzyme A
from the TCA cycle giving its coenzyme
A residue to acetoacetate, which results
in the formation of acetoacetyl coenzyme A.
This reaction happens in the mitochondrion of the cell.
At step four acetyl coenzyme A is
converted by beta ketothiolase into two molecules
of acetyl coenzyme A. And again, we're
going to need another coenzyme A group
to come in at this point as part of the beta ketothiolase
reaction.
Remember that beta ketothiolase is
the last enzyme that's operative in beta oxidation
of fatty acids.
Here it's doing the same chemistry
that it does in beta oxidation.
It splits acetoacetyl CoA into two acetyl CoA molecules.
And in steps five and six, those molecules
integrate into the TCA cycle.
In the TCA cycle they're oxidized to carbon dioxide
with the generation of energy.
Let me review for a minute before going
into a physiological scenario.
Way over to the left at step one,
the liver has made acetyl CoA and packaged it
into two ketone bodies, acetoacetate
and beta hydroxybutyrate.
They travel in the blood to target tissues,
for example, the muscle, or heart, or the brain.
In these target tissues these ketone bodies are internalized,
converted to acetoacetate, and then to acetoacetyl coenzyme A
and then ultimately to several molecules of acetyl coenzyme A.
The acetyl coenzyme A that started in the liver,
ends up in the target tissue and then can
be used to generate energy.
This is a particularly important reaction under conditions
of starvation and diabetes.
Let's now look at panel b of storyboard 24.
As you know, I like to look at physiological scenarios
because at least to me, they helped make biochemistry real.
The scenario I want to look at is that of diabetes.
In Type 2 diabetes, which is the type that I have,
my cells have become resistant to taking up glucose.
My cells are insulin insensitive.
After a meal I have very, very high concentrations
of glucose in my blood, because the cells of my tissues
are not capable of taking it in.
Hence, if I do not take my anti-diabetic medication
the sugar concentration in my blood
stays high, which leads to some of the medical complications
of diabetes.
More on that later.
Given that there's a lot of glucose in my blood,
but it's not getting into my cells,
my cells are actually in a technical state of starvation.
Take a look at the pathway I've drawn in panel b.
Glucose on the left is not getting into the cell.
I've used broken lines for the pathway from glucose
to pyruvate and then from pyruvate in the cytoplasm
into the mitochondrial matrix.
These broken lines are meant to indicate
that the pathways involved are just not very active.
The sparse activity of these pathways
means that acetyl CoA levels are becoming somewhat
limiting in the mitochondrion.
Because pyruvate is also limiting,
the enzyme pyruvate carboxylase doesn't
have sufficient pyruvate in order
to maintain the oxaloacetate concentration
within the mitochondrial matrix.
Once again, oxaloacetate is the TCA cycle intermediate
that that's at the lowest, that is micromolar concentration.
I'm focusing here on the liver, although I
should add at this point that all tissues are
similarly limited in the pathways indicated
by the broken lines.
The liver's response to sensing this limitation
in carbohydrate processing is to either take in lipid
or to break it down from internal stores,
for example, triacylglycerides in order to produce acetyl CoA.
But because oxaloacetate is limiting,
the step at beta ketothiolase backs up,
producing a large amount of ketone bodies.
The ketone bodies are produced in excess,
so you can see them escaping into the mitochondrion
and later out of the cell, and they go off into the blood.
Consequently, the liver of diabetics
produces a lot of ketone bodies, because it senses
that the body is starving,
To the right of panel B, I have some blood chemistry values
that are of relevance to diabetics.
In a non-diabetic person, blood sugar concentrations,
that is blood glucose is maintained
at about 100 milligrams of glucose
per 100 milliliters of blood.
When I was diagnosed with diabetes,
my blood sugar was over 300 milligrams per 100 milliliters.
As I recall the symptoms were disorientation.
I couldn't walk very easily, I was thirsty,
and I urinated a lot.
Normal ketone body concentrations
are less than 0.2 nanomolar.
In a severe diabetic situation, your ketone body concentrations
could be 15 to 25 millimolar and the pH of your blood
could drop from the mid 7 range down to about 6.8.
The kidney responds to the high concentration of glucose
and the high concentration of protons,
that is the low pH, by increasing urine volume output
in order to try to urinate out the glucose and protons.
The results are that the diabetic becomes excessively
thirsty which again is one of the biomarkers
or symptoms of the disease.
The classic historical treatment of diabetes
is to give insulin, which will push more glucose into the cell
and thus offset the biochemical defect that leads ultimately
to ketone bodies and to the high concentration of glucose
in the blood.
Aside from giving insulin by injection
there are other medications that will
result in a sort of reactivation of the beta cells
in the pancreas in order to produce more insulin naturally.
Alternatively, there are medications
that will block gluconeogenesis and thus
stop the ability of the liver and other gluconeogenic organs
from producing glucose.
So by blocking gluconeogenesis, one
can lower the glucose concentration of the blood.
As you see there are many, many ways to treat this disease.
Let me add that it can be a very debilitating disease, leading
to blindness, amputation, and cardiovascular difficulties.
It's a good idea to try to avoid the risk
factors for this disease.
It's not fully preventable at least
in people who come from families in which nearly everybody gets
it, for example, my situation.
But by avoiding risk factors you can push off the date of onset
by many years.