Modeling Alcohol Abuse and Liver Disease – Bin Gao, NIH IRP

>>As you know, drinking too
much alcohol may cause you liver damage and it leads to liver
cirrhosis and then cancer. So, you know, the
goal of our laboratory at the National Institute
of Health is trying to understand how alcohol
drinking causes liver damage and liver cancer. Particularly we want to know
how immune cells, you know, participate in alcohol-induced
liver injury; how genetic factors, dietary
factors, aging, etc., you know, modulate alcoholic liver
disease and injury.>>And so I’m working
on the new mouse model of alcohol liver disease
that we recently developed. And so this model incorporates
both chronic and binge drinking to mimic the drinking
pattern in humans. And it closely replicates
some features of the human alcoholic
liver disease. And so this new model can be
used to study the pathogenesis of alcoholic liver disease
and can also be used to explore new therapeutic
targets for this disorder. So those cells are
our mouse hepatocytes. And we are using
them to incubate with different inflammatory
cytokine or with alcohol to study the response of
these cells to these stimuli.>>So I was interested
in looking at a few different
dietary aspects. For example, here in
America you always hear about the Western diet
and how that’s high in fat and high in sugar. So I was interested
in looking at that, but I was also interested
in looking at other things, for example, high-fat diet
by itself; high sugar, because we have the
issue with the sodas and the high fructose
corn syrup; and then also high cholesterol
because that also seems to be an issue in
the American diet. So I’m very interested in seeing
how those different dietary aspects might affect
the progression of alcoholic liver injury. So what we have here are
different diets using our rodent model. So at the very end, those
light brown pellets, that’s just the regular diet
that the mice are usually on. Next to that we have
a very high-fat diet. These light-colored pellets
here are the Western diet. So those are high in
fat, high in sugar, and slightly different
fat composition as those. Here the light blue is
a high-sugar diet alone. And then I was also interested
in looking at the combination of high fat and high sugar, so
that’s with the pink pellets. And then here, the light green, we have the high-cholesterol
diet. And then after these mice
feed on these for 12 weeks, then I will give them
binge alcohol and see how that affects the
alcoholic liver injury.>>So in order to look at the
overall morphology of liver, we first have to
embed them using wax. So these are liver samples, and
they have already been fixed. So now what Dr. Matthews is
doing is she’s embedding them into wax. And once they’re all placed in
order, she’s going to put them in a platform that is cold, that’s going to solidify
the wax. And in order to get slices, then
you’ll have to use a microtome and put them into a slide. And then you can do different
types of stainings in order to visualize whether there
is fat in the liver or just to get a quick look at
the overall morphology. So this is a hepatocyte
in a liver cell. This is what we consider to be
a nicely arranged morphology because hepatocytes are
a type of liver cells, and they’re arranged
in a nice order. So when you have
ethanol exposure, that array is actually
disorganized and becomes disregulated
due to the lipid or fat accumulation
in the liver.>>One of the major
projects in our lab is trying to study how genetic factors may
affect alcoholic liver disease. For example, one
of the key enzyme to metabolize alcohol is
aldehyde dehydrogenase, ALDH2. In Asia, 50% to 60% of Asian
population actually have ALDH2- very low activity. So those people who are drinking
alcohol may develop a high level of aldehyde, causing the
flushing syndrome — a red face. So we actually are trying to understand how this enzyme
deficiency may affect the liver injury, liver inflammation,
even liver cancer. So hopefully we study this
animal model, then we may move to the clinical study to
identify the function of ALDH2 in the liver inflammation
injury and cancer.>>This one is low FSC, SSC. This is the lymphocytes. And then here the SSC is much
higher because that means that the cell have lots of vascular structures
and neutrophils.>>Okay.>>So my work is just to confirm
the finding by our colleagues to verify the role of immune
cells in the development of alcoholic liver disease. So by collaborating
with Dr. [inaudible] in Temple University, we
have generated a special transgenic mice. By using the mice, when
we injected some drug, we can specifically kill
some certain immune cells, like neutrophils here, by
injecting mice with the drug. It can kill the neutrophils in very short time,
like, ten minutes. Traditional medicine can
also do that, but it takes around two or three days. Our technique is much
faster and powerful. So first we should verify
the role of neutrophils in the development of
alcoholic liver disease. And maybe other cells are also
involved, we are planning to do that to different kind of
immune cell to see what happened to alcoholic liver disease. And here, for the hepatocytes, we can start the
liver regeneration. So when the hepatocyte
was depleted and we see how long it will
take for the liver to recover, to regenerate, and we can
start the whole process. We have a traditional model to
start the liver regeneration, but this one provides
a new model because traditional
one just needs surgery. This one only just-
inject some drug. So, that’s advantage. When you inject something, you
do see something changed — that’s very, very exciting. No one sees that before. I’m the first one to see that. It’s really, really exciting.>>Alcoholic liver
disease is special. There’s a rare form of
alcoholic liver disease. It’s very difficult to treat. And there’s no FDA-approved
therapy for this disease. The number of alcoholic liver
diseases in the US is- more than 2 million Americans
who are affected by alcoholic liver disease. So the final goal
of our lab is trying to identify effective
therapy to treat this disease. Recently we have demonstrated that interleukin-22 is
a key survivor factor for the liver cells. Those study result-
it’s being translated into the clinical study. Interleukin-22 is mainly
produced by immune cells. But the immune cells
do not have a receptor for this interleukin-22. So interleukin-22 does not come
back to target immune cells; instead, they are specifically
targeting liver cells, like a hepatocyte. So the side effect of interleukin-22 treatment
should be very minimal because they are very
specific- target hepatocytes and other epithelial
cells, not immune cells. The clinical trial for the
interleukin-22 for the treatment of alcoholic liver disease
is under the investigation. Hopefully in the future, we
have some drugs that can be used for the treatment of alcoholic
liver disease so it’s beneficial for the liver disease patient.

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