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We are the paradoxical ape,
bipedal, naked, large brain,
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Hello. My name is Joe Hacia and I'm on
the faculty at the Keck School of Medicine at USC.
Today, I'm going to be talking
about by phytanic acid metabolism.
Our objectives are to discuss
the bioenergetics challenges of
a larger brain size in
humans relative to non-human primates.
To describe anatomical differences and the guts of
human and non-human primates
relevant to energy metabolism.
To discuss how the branched chain fatty acid,
phytanic acid can be obtained through
dietary sources and catabolized in primates.
Finally, to relate by phytanic acid levels measured in
blood specimens to
human and non-human primate diets and physiology.
One of the overarching questions that has
an interest in MyLab and many others is,
what are the metabolic repercussions
of a large human brain?
As a result of this over the past several decades,
there have been numerous hypotheses.
The most impactful, in my opinion,
is the Expensive-Tissue Hypothesis,
that was formulated by Leslie Aiello at
the University College London and
Peter Wheeler in Liverpool John Moores University.
They related gut in brain size with the idea that,
suggestion that the metabolic requirements
of a relatively large brains,
are offset by a corresponding reduction of the gut.
In this particular nice figure,
summarizes it from their paper.
We're looking at the direct connection
to the smaller gut with the larger brain,
providing increased energy availability to
fuel the metabolic needs of the larger brain.
This is also tied in with higher quality diets,
which can increase energy availability
and reduce bulk and
costs more rapid assimilation of
foodstuff in the smaller gut.
This is also related to
the evolution of more complex foraging behavior.
In addition with a higher-quality diet,
there's been a whole field of research about
the evolution and the development
of meat eating and cooking in the human diet,
and how that can potentially
impact the energetic needs of a larger brain.
Now, the Expensive-Tissue Hypothesis has been
subjects and much discussion
like any other good hypothesis.
It has led to
many different modifications in
different alternative hypothesis.
However, I am very
impressed with the impact that is
made in this particular field,
because it really spotlighted
another difference in
human and non-human primate anatomy.
That is that of the digestive tract,
which has both similarities
and differences across humans,
orangutans and humans as shown in this particular slide.
You're seeing a very similar architecture
of the small stomach,
which is then connected obviously,
to the small intestine,
and in the large intestine over here,
in all of these three panels.
However, you can see differences in the proportions
of the gut or
the relative proportions of
these various components of the gut.
In the work of Katharine Milton in UC Berkeley,
she had a nice paper in a journal on nutrition in 2003,
where she quantified the relative gut volume
in gibbons, siamangs,
orangutans, gorillas, chimpanzees, and humans,
at the stomach, small intestine,
cecum, and colon.
I want to highlight over here that
the massive differences are
dramatic differences, I should say,
and relative gut volume of
the small intestine in humans
relative to the other non-human primates in
this particular chart here as well as the deamination of
the colon size in humans relative to the other species.
One of the questions is, begs is,
how does this relate to energy metabolism in primates?
Well, it turns out the microbial fermentation
in human and great ape hindguts,
which is going to also be comprised of
the colon and large intestine.
They're involved in breaking down
complex carbohydrates that are
not processed and absorbed in the small intestine.
The major products of
hindgut fermentation short chain fatty acids,
which are energy yielding substrates for
colonic mucosa that regulate
its growth and blood flow and
promotes sodium and water absorption.
Now, great apes can, in the wild,
derive significant levels that are
total daily metabolic energy from fiber fermentation,
as shown over here in wild chimpanzees,
orangutans in Western gorillas,
and ranges from seven percent up to about 60 percent,
mainly in the higher area of that range.
In contrast, humans on
Western diets are thought to obtain
no more than 10 percent of
their daily energy needs through hindgut fermentation.
It's likely higher in populations with
lower-quality diets and instances
of small intestinal malabsorption.
Now, what about other products of gut fermentation
of plant materials in
addition to these short chain fatty acids?
Well, phytanic acid is another product
of gut fermentation of
plant materials in certain mammals.
The star that show here is chlorophyll,
which is a most abundant molecule in nature,
which is going to be a major component of
the foodstuffs of individuals who
are ingesting plant materials.
It turns out in ruminant animals such as a cow,
with the gut fermentation of
plant materials can break down
chlorophyll by the liberation
of this particular side chains of phytol.
This is happening by the activity of microbes in
the guts of these ruminant animals.
Phytol itself, in all land mammals surveyed
today can be oxidized to a molecule called phytanic acid,
which is a branched chain fatty acid,
which is stored in room and its fats,
and is also present in certain dairy products.
Chlorophyll itself can also be in
the marine food chain through
the digestion of phytoplankton by zooplankton and krill,
which is then converts it just similar
to land mammals, the phytanic acid.
Once it gets in the food chain,
it becomes present in certain fish,
marine mollusk, and whale fats.
Now. In contrast, humans cannot produce
appreciable amounts of
phytanic acid by chlorophyll catabolism.
This is classic work in
the 1960s that individuals who are actually fed
radio-labeled chlorophyll and shown
that it passes through
the system with limited modifications if any.
Humans themselves though can obtain phytanic acid from
marine and terrestrial food chain and phytanic acid,
though provides known health benefits to humans.
This is the key here that obtaining
phytanic acid from the marine and terrestrial food chain,
knowing that humans historically have had
much greater consumption of meat and
marine products relative to that of other great apes.
This is a brief depiction here of
a simplified digestive system of
a cow who's ingesting grassy material,
which would then cause
their exposure of chlorophyll in the rumen
then by microbial activity to be converted
to fight all and then stored in fats as phytanic acid.
Now, phytanic acid itself,
is broken down in humans
and other non-human primates in the liver.
It's broken down in
a metabolic organelle called the peroxisomes.
Phytanic acid is the branched-chain fatty acid
has an unusual mechanism of being catabolized.
It actually first gets converted to
a CoA iyase which gets imported in itself.
This CoA iyase into the peroxisome and
the activity of an enzyme called
phytanoyl CoA hydroxylase by h,
which I'm going to get back to in a few moments,
is involved in converting into
some downstream metabolites that
are then eventually converted to
a molecule called prostatic acid.
Prostatic acid itself is now capable of
being metabolized through standard beta oxidation.
Now, this particular pathway I've shown here
is the Alpha oxidation of fatty acids,
which is an unusual specialized pathway.
Beta oxidation is more than norm and
Beta oxidation in the peroxisomes of prostatic acid
leads to medium chain
fatty acids that can be exported into
mitochondria for a beta oxidation
to carbon dioxide and water.
Now, phytanic acid,
as I mentioned, has no known health benefits.
However, phytanic acid,
over accumulation can be toxic in humans,
which is interesting because we're thinking of
humans as being the species that
has meat and marine products in
their food supply over historic time-frames.
Adult Refsum disease is
a recessive disorder with an incidence
about 1 million individuals in various populations.
It is caused by loss of function variants in
the PHYH gene is phytanoyl-CoA hydroxylase gene.
People with Adult Refsum disease have
impaired phytanic acid catabolism and it can
accumulate stores of phytanic acid
in various tissues due to dietary exposure.
This can lead to a polyneuropathy, loss of vision,
hearing and smell, ataxia,
skin condition called exocytosis.
Some skeletal involvement as
well, some cardiac involvement.
What I'm highlighting here is the Global DARE Foundation,
which has been founded by patient advocates to be able to
promote research into Adult Refsum disease.
We have an interesting now connection between
phytanic acid which is present in the diet and
the fact that there is a need to metabolize
phytanic acid properly or else there can
be severe health consequences.
We became interested in looking
at the relative abundance of
phytanic acid levels in
human and non-human primate tissues.
The easiest tissue to obtain were red blood cells,
the most readily available.
What we did by our collaborators at
the Kennedy Krieger Institute
looked at the relative abundance of
fatty phytanic acid in red blood cells relative to
all other fatty acids that were present in the specimen.
We looked at a collection,
a cohort of individuals,
including humans, apes,
old world monkeys and new world monkeys.
What we've shown here are the numbers of
individuals in each individual category.
In humans, we had included individuals on
vegan diets for over a year as well as on western diets.
The individuals on western diets have about
a 50 to 100 milligrams phytanic acid daily intake,
whereas those on the typical vegan diet have
less than two milligrams daily phytanic acid intake.
All the captain non-human primates here
have a very low phytanic acid diet,
very similar to that of in magnitude of
phytanic acid intake relative to
vegans of about two
less than two milligrams daily intake.
In this box plot you can see
very readily that individuals,
humans on vegan diets by far had
the lowest percentage of
fatty acid in phytanic acids in
the red blood cells relative to other fatty acids.
This is remarkably consistent across
all the other individuals on
this particular, in this cohort.
The western diet individuals were actually the humans
showed higher levels of
phytanic acid as would be predicted,
but there are other species including orangutans,
which are on very low level phytanic acid intake in
their diet yet they have
remarkably higher levels of
phytanic acid in their red blood cells.
They're attaining it in one way or another
through their diet in a way that humans cannot do so.
Now, the rates of catabolism of phytanic acid in
cultured human and non-human
primate skin fibroblasts are similar.
Here are individuals, human chimpanzee,
bonobo, gorillas and orangutans.
Measuring the rate of
phytanic acid oxidation when
radio-labeled lipid was added to the culture medium,
and what you're seeing here is that there is overlap in
the relative oxidation of
rates of phytanic acid and needs particular species.
It's very similar also in phytanic acid,
which you might recall as
a downstream metabolite phytanic acid metabolism.
All species so to
robust cellular metabolism of
phytanic and prostatic acid,
but we did find something remarkable that there are over
two-fold more abundant higher levels of
PHYH messenger RNA expressed
in human relative to a chimpanzee,
bonobo and gorilla fibroblasts.
They might recall PHYH when the key enzymes
that is involved in phytanic acid catabolism.
To explore this a little bit more,
back in 2010, we did a re-analysis,
a transcriptomic data from tissues
obtained from chimpanzees and humans,
which were published by Svante Paabo's group.
We looked at exclusively at the expression levels of
genes which are involved in
phytanic acid Alpha oxidation,
which is the early stage of
phytanic acid degradation and peroxisomes,
followed by peroxisomal acid Beta oxidation,
which is the later stage of
phytanic acid metabolism in the peroxisome.
We also looked at the genes that are regulated
by a transcription factor called PPAR Alpha,
where phytanic acid is known to
actually be involved in regulating its activity.
When we looked across these tissues from liver,
heart, brain testes, and kidney,
what we found was something that was quite
remarkable in our opinion, was that there is,
here highlighted in orange are differences in
gene expression that were
significantly different across the species.
In this particular case in orange,
we had higher levels of
human transcripts relative to those from chimpanzees.
In green, would be higher levels and transcripts in
the chimpanzee relative to
the human specimens and those,
they've all had Bonferroni
corrected p-values of less than 0.05.
This is a robust analysis.
We're seeing higher levels of genes such
as expression of PHYH in liver,
heart and brain, and kidney in
humans relative to chimpanzees.
We're also seeing higher levels of
paroxetine of the transcripts related to phytanic acid,
Alpha and Beta oxidation in both liver,
heart, and testes.
Correspondingly also see higher levels
of genes that are regulated by
the transcription factor PPAR Alpha
in these particular tissues as well.
In conclusion, relative to humans
diverse cap that non-human primates have
higher red blood cell phytanic acid levels when
fed plant rich phytanic acid deficient diets.
Human and great apes,
cultured skin fibroblast all show
robust phytanic acid metabolic activity.
Our favorite hypothesis is
that unlike humans diverse cap that
non-human primates could obtain
substantial amounts of phytanic acid
from gut microbial degradation of
ingested chlorophyll and
red blood cell phytanic acid levels could provide
a bio-marker of gut fermentation activity useful for
evaluating the digestive health
of captive non-human primates.
I just like to briefly acknowledge our collaborators,
including individuals in my lab at USC and
those collaborators at Rutgers University,
Alamogordo Primate Facility, Kennedy Krieger Institute,
Zoological Society of San Diego,
the Southwest National Primate Research Center,
funding through NIH.
Also I have a special shout-out to
the Global DARE Foundation which is doing admirable work,
trying to find better treatments for
individuals with Adult Refsum disease.
Thank you very much
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