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Metabolic dysfunction-associated steatotic liver
disease (MASLD), previously known as "non-alcoholic
fatty liver disease", affects about 25% of the
global population. Its severe form, metabolic
dysfunction-associated steatohepatitis (MASH), can
lead to liver fibrosis and even liver failure. With
only one approved treatment currently available,
finding solutions for MASLD and MASH is crucial.
MASLD and MASH are closely related to obesity, poor
diet, and lack of exercise. These conditions lead to
fat accumulation in the liver, which can cause
inflammation and scarring. Over time, this can
progress to fibrosis and cirrhosis, resulting in
severe liver damage. Despite their prevalence, there
are limited therapeutic options available for people
suffering from MASLD and MASH. Another problem is
the reduced levels of a molecule called NAD+
(nicotinamide adenine dinucleotide), which plays a
key role in many cellular processes, including
energy production, DNA repair, and inflammation
control. In MASLD/MASH, NAD+ levels drop, and this
contributes to liver damage and disease progression.
Restoring NAD+ levels could potentially stop or even
reverse this damage. A team of scientists has now
shown that inhibiting an enzyme called ACMSD could
be the answer. ACMSD
(α-amino-β-carboxymuconate-ε-semialdehyde
decarboxylase) is mainly found in the liver and
kidneys and is involved in breaking down the amino
acid tryptophan and limiting the production of NAD+.
By blocking ACMSD, the researchers found they could
increase NAD+ levels in the liver, which in turn
reduced inflammation, DNA damage, and fibrosis in
mouse models of MASLD/MASH. The researchers used
several models, including rodent liver cells and
human liver organoids i.e., lab-grown mini-livers.
The results were promising: Inhibiting ACMSD
significantly boosted NAD+ levels, particularly in
the liver, where ACMSD plays a critical role in
energy metabolism and protects against DNA damage.
This increase in NAD+ reduced inflammation, and
reversed fibrosis and DNA damage in the livers of
the treated mice. Meanwhile, they also found that
inhibiting ACMSD in human liver organoids also
reduces markers of DNA damage. The findings indicate
that blocking ACMSD could be a potential new therapy
for MASLD and MASH. Boosting NAD+ production in the
liver could protect against the severe damage caused
by these diseases, reducing the likelihood of
progression to cirrhosis. This approach also
highlights the importance of metabolic pathways in
liver disease and offers with ACMSD, a new target
for drug development. |