The
unique mouse model captures all three hallmarks of excess fat,
inflammation and scarring in the liver, opening the doors to better
understanding and development of treatments for NASH, said the study
leader. The researchers published their results in the journal Nature Communications.
Nonalcoholic
fatty liver disease affects an estimated 25% of Americans, according to
the National Institutes of Health, and up to a third of patients will
develop inflammation and scarring as well, falling under the NASH
classification.
“It’s
not really clear why certain people end up developing NASH,” the author
said. “So far, there haven’t been any genes that have been directly
linked to NASH. It’s been thought of as a progression: After the liver
is injured or it becomes fatty, if you don't check it, it’s going to
progress toward NASH. But not everybody with fatty liver develops NASH
and it seems random who does, so it’s very confusing as to why this
happens.”
The
other problem making NASH research difficult is the lack of good animal
or cellular models for it, the author said. While some models
incorporate one or two of the symptoms, and then other damage inflicted
to mimic what is seen in NASH patients, they don’t give an accurate
portrayal of the disease.
The
group began studying SRSF1, a protein that assists in splicing RNA in
the cell, to study its splicing activity. They bred a line of mice that
were lacking the gene to learn about its splicing activity. The mice
soon spontaneously developed all the symptoms of NASH.
“We
were very excited to see this, as we thought, this could be a model for
the disease. But first, we had to figure out the mechanisms of why
SRSF1 was connected to liver disease,” said the first author of the
study.
The
researchers found that the mechanism was not related to SRSF1’s
splicing activity, as first thought, but because it protected against
DNA damage in the liver during the process of DNA unwinding so its code
can be transcribed into RNA. Without the SRSF1 protein, liver cells
began to shut down.
“What
happened was the cell wanted to die because of the extensive damage
that was happening to the DNA. But it didn’t have the energy for regular
programmed cell death processes. The damage was so severe that
everything just shut down,” said the senior author.
It
was the opposite of the pathway that had been assumed, the author said:
Instead of excess fat leading to cell damage, the cell damage came
first, and fat built up as a result of the cells not being able to
perform their function of packaging up digested fats. Inflammation
increased as the immune system tried to clear away dead and dying cells,
and then fibrosis appeared as scars formed over patches of dead tissue
to try to hold the liver together. The researchers saw this same
sequence in both the mice without SRSF1 and in human liver cell lines
depleted of SRSF1.
“These
findings tell us that the genome of the liver cells has to be properly
maintained,” the senior author said. “Liver cells are encountering
toxins and DNA damage more than any other cells in our body. This study
illustrates that when liver cells encounter excessive DNA damage, these
NASH symptoms develop. SRSF1 plays a protective role against that. It
acts as a guardian of the liver genome.”
The
researchers hope the mice will aid other researchers studying NASH,
both in terms of understanding the disease and in exploring potential
treatment targets.
“We
want to see whether there are certain conditions where SRSF1 has been
inactivated in some way in human livers or other animals,” the author
said. “Maybe there are some toxins or medicines or other environmental
pollutants, for example, that could cause inactivation of the SRSF1
gene. Figuring out the triggers that cause silencing of SRSF1 could
point to treatment targets, and whether things like anticancer drugs
that prevent DNA damage could be applied here. It’s interesting to note
that many NASH patients develop cancer as well. Is that linked to the
DNA damage?”
The
researchers also plan to explore whether other genes protect DNA in
this way, and whether damage to any of them could cause NASH pathology
as well.
https://www.nature.com/articles/s41467-023-35932-3
http://sciencemission.com/site/index.php?page=news&type=view&id=publications%2Fsplicing-factor-srsf1_3&filter=22