Alright, and we’re back! So our story so far has covered what ketone bodies are and
how they are formed, and some of the ways we can turn our bodies into ketone
body creating machines. This
article will look further at some ways the creation of ketone bodies is
regulated. As I did with the last article
I will put out the “lots of science” disclaimer on this article. This one will be more technical than
the last one was, it is just the nature of the beast when you are talking about
some of these complex biochemical pathways.
I know that all the weird letters and numbers that represent
proteins in our body don’t really mean much to most people, but remember they
are really just designations for various receptors our body uses to recognize
each specific chemical in our body.
It is important to remember that things in our body usually can’t just
go in and out cells and tissues as they please. Few things in our body just happen. They are all controlled by various
receptors and proteins that help to move them. So, while I will be presenting the actual biochemistry here,
I hope I can bring each section home at the end and give everyone a take home
message that will be meaningful.
Insulin
Well, I am sure at least a few of you out there thought we
would be seeing our old friend insulin at some point. For those of you who might not be familiar with insulin, it
is the hormone secreted when glucose is eaten, and has two main functions:
deliver glucose to tissues that need energy, and inhibit lipolysis (fat breakdown).
Insulin has a marked inhibitory effect on ketogenesis, as you would guess if it
is a hormone associated with glucose.
As we can see from this figure from a study on the rate of ketone
appearance (TKB Ra) in both lean and obese humans, those patients with higher
insulin levels have a lower rate ketogenesis (1).
How does insulin inhibit the production of ketone bodies? Well,
there are three main enzymes that are the “rate limiting steps” for different
parts of ketogenesis, and insulin has an effect on all three.
(By rate limiting steps all I mean is that in a certain
biochemical pathway there will be one reaction that has a larger effect on the
total outcome than the others. For
instance, if we have a reaction of A to B to C; the reaction of A to B might
take longer or require a special enzyme, while the reaction of B to C would
just happen when enough B is present.
In this case A to B would be the rate limiting step, as it has a special
limiter that the total reaction of A to C can’t work without.)
The first enzyme that helps to control ketogenesis that
insulin works on is Hormone-sensitive lipase (HSL). HSL is found in the adipocytes, and is the rate limiter for the
breakdown of our stored fat (triglycerides) into free fatty acids, which can
then be transported to the liver and be further broken down into the
acetyl-CoA’s needed for ketogenesis (2). When insulin is present it “dephosphorylates” the HSL, which
is just a fancy way of saying it deactivates the enzyme in this case. Once
deactivated triglycerides can no longer be broken down into fatty acids, and
our substrate for ketogenesis stays tied up in the adipocytes.
The next enzyme that insulin has an effect on is Acetyl-CoA
Carboxylase (ACC). ACC is present
in our liver and catalyzes the production of malonyl-CoA from our precious
stores of acetyl-CoA; this malonyl-CoA is then used to create new fatty acids
for storage (3). Not only does malonyl-CoA use up some
of our acetyl-CoA stores, but it also decreases the amount of fatty acids that
move into the mitochondria, which is where all ketogenesis happens. Without fatty acids in the
mitochondria, ketogenesis cannot occur.
How does insulin act on ACC? Well since ACC is a potent inhibitor of ketogenesis by
decreasing our acetyl-CoA stores and reducing fatty acid transport into the
mitochondria, insulin increases ACC activity (4). Insulin performs this by inhibiting the
AMPK pathway, which then prevents the phosphorylation of ACC. In
this case, NOT being phosphorylated activates ACC, and thus decreases
ketogenesis.
The final enzyme that insulin has an effect on that helps
control ketogenesis is HMG-CoA synthase (HS), which you hopefully recognize
from the first article as the enzyme that controls the first step in
ketogenesis, the joining of two acetyl-CoA molecules. Insulin inhibits ketogenesis by decreasing the transcription
(the making of the protein itself) of HS by reducing the effect of a potent
transcription factor for HS, FKHRL1 (5). Wow, that’s a mouthful, let’s break it
down just a bit more.
A transcription factor is just something that will stimulate
the production of specific protein, HS in this case; it does this through
interactions with the DNA itself.
The transcription factor here is FKHRL1, and when it interacts with your
DNA, it will increase the expression of HS. However, this interaction is inhibited by insulin! Without HS expression we cannot join our
acetyl-CoA molecules, and thus will not produce any ketones.
So, we can see that insulin has many effects on the systems
that control ketogenesis. The reason I said that I think these mechanisms of
regulation are similar to the ones in the last article is because insulin is
intricately tied to our glucose status, so a high-carb diet is going to prevent
ketogenesis two ways, through the physiologic processes we talked about last
time, and through raising our insulin levels.
Glucagon
Glucagon is typically considered a starvation hormone, as
its release is stimulated by low blood glucose levels (6). It is made in the pancreas, and is also inhibited by high
blood glucose levels and insulin.
Glucagon is potent stimulator of ketogenesis, and does this through
interactions with the same three enzymes as insulin. Since we already know the functions of these three enzymes,
and the effects of glucagon are almost just the opposite of that of insulin, we
should be able to go through this pretty quickly.
First, for HSL, glucagon acts to phosphorylate the enzyme. Phosphorylation
can activate an enzyme, and that is
exactly what happens here. Glucagon
stimulates the phosphorylation of HSL, and once activated will initiate the
breakdown of triglycerides from the adipose tissue for use in making fatty
acids. Glucagon does this by
stimulating cyclic AMP-dependent protein kinase, which is known to
phosphorylate and activate HSL (7).
Now here is where things get a bit confusing. Glucagon will inhibit ACC by causing phosporylation of the enzyme. Wait, what? Didn’t you say earlier that phosphorylation activates them? Well, yes that does happen through certain
pathways but when others are stimulated they can cause a deactivation of the
enzyme, it all dependent on where they phosphorylate/dephosphorylate on the
enzyme. In this case, the
phosphorylation occurs at a site that will stop the function of ACC. Glucagon
facilitates this by activating AMPK, a protein that will phosphorylate and
inactivate ACC (8).
With ACC inhibited fatty acids are free to be transported into the mitochondria
to be used for ketogenesis.
Finally, glucagon plays a large role in the regulation of
HS. Phosphorylation and
dephosphorylation are not the only mechanisms to control enzymes in our
body. Some of you may have heard
of acetylation, which is attaching one of our acteyl-CoA groups to an enzyme or
even DNA to activate/deactivate it.
However, HS is intricately regulated by succinylation. When HS is succinylated it is deactivated,
and glucagon will prevent the succinylation of the enzyme, thus keeping it
activated (9).
As we can see ketogenesis is highly regulated by both
insulin and glucagon, who, in turn, are regulated by opposing blood glucose
levels. Insulin is activated by
high blood glucose levels, where as glucagon is activated by low blood glucose
levels. With all this information
on the biochemical control of ketogenesis we can see just how important it is
to keep our glucose levels low if we want to maintain ketosis.
I know this is a lot of information, but I found a great
review article that has a nice table that summarizes all this information
nicely (10).
This table skips a lot of the intermediate biochemistry and
just gives you the straight effect of our three enzymatic regulators, and the
effect of insulin and glucagon on them.
I think it is a great summary of all the information above.
There are many other hormonal/enzymatic regulators of ketosis. We can see from these abstracts that
norepinephrine, epinephrine, and thyroid hormone all seem to play a role in
ketosis by their effects on lipolysis (fat breakdown) (11, 12). Norephinephrine increases lipolysis,
and thus ketogenesis, but also seems to increase liver ketogenesis.
While thyroid hormone does appear to increase ketogenesis
through increasing lipolysis, it is important for hyperthyroid patients to keep
a watchful eye on both thyroid hormone levels and ketone body levels, as there
are several case studies in which severe increases of thyroid hormone cause
ketoacidosis and then cardiac arrest (13, 14,) While this appears
to be very rare, it is definitely something to keep in mind when determining
your own optimal diet.
Summary
Well, yet again we have covered a ton of information in this
article. The control ketone body
creation is an intricate process within our body, and is regulated in a variety
of ways, and through many hormones.
- Insulin is activated by a rise in blood glucose levels, and has an inhibitory effect on ketogenesis.
- Glucagon is activated by a decrease in blood glucose levels, and increases ketogenesis
- Hormone-sensitive lipase is a main regulator of ketogenesis by controlling the break down of triglycerides in adipose tissue. It is inhibited by insulin and activated by glucagon.
- Acetyl-CoA Carboxylase is a main regulator of ketogenesis by stopping the transport of fatty acids into the mitochondria, and creating malonyl-CoA from acetyl-CoA. It is activated by insulin and deactivated by glucagon.
- HMG-CoA synthase is THE main regulator of ketogenesis, as it is the step in the pathway that joins two acetyl-CoA molecules. It is inhibited by insulin and activated by glucagon
- Other hormones such as norepinephrine, epinephrine, and thyroid hormone have been shown to affect ketogenesis.
While these last two articles may have seemed too
complicated to some, I think recognizing this interplay between so many body
systems is important, not just because of its role in ketosis, but its role in
overall energy homeostasis. All of
the regulation mechanisms above mark a step in the process of your body sensing
its energy state, and these regulators are key to keeping our health in check.
This one is pretty long already, so I think I will turn the final part of regulation into a separate article. We have to cover one of the main signaling pathways for controlling ketosis, so we will go over that hopefully tomorrow.
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