Development of fatty liver disease under a healthy diet
Date:
January 18, 2022
Source:
Max Planck Institute of Molecular Cell Biology and Genetics
(MPI-CBG)
Summary:
A new study identifies two genes, previously reported to be
involved in cancer, as regulators of the metabolic state of the
liver. Alterations in these genes influence the likelihood of
developing fatty liver disease.
FULL STORY ==========================================================================
A new study identifies two genes, previously reported to be involved in
cancer, as regulators of the metabolic state of the liver. Alterations
in these genes influence the likelihood of developing fatty liver disease.
==========================================================================
The epidemic of obesity worldwide has increased the risk of accumulating
fat in the liver, a preamble to liver inflammation and liver disease. Yet,
a still intriguing paradox is the development of fatty liver in lean
and normal-weight individuals and in individuals following a healthy
diet. Scientists know that two genes, RNF43 and ZNRF3, are mutated
in liver cancer patients. However, their role in the development
of liver cancer was unknown so far. Researchers at the Max Planck
Institute of Molecular Cell Biology and Genetics (MPI-CBG) in Dresden,
Germany, describe now that a loss or mutation of these genes causes
an accumulation of lipids and inflammation in the liver in non-obese
mice fed a normal diet. These genetic alterations not only increase the accumulation of fat but also the number of liver cells (hepatocytes)
in proliferation. In human patients, these alterations also increase
the risk of developing NASH and fatty liver and reduce the patient's
survival time. These findings might facilitate the discovery of people
at risk and could promote novel therapeutic interventions and better
management of the disease.
The liver is our central metabolic organ, which is vital for
detoxification and digestion. Chronic liver diseases, such as
cirrhosis, non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH, inflamed liver), as well as liver cancer, are on
the rise worldwide, with a combined mortality of two million individuals
dying each year. It is therefore more important than ever to understand
their causes and the underlying molecular mechanisms of liver diseases in
order to prevent, manage, and treat these increasing patient population subgroups. Previous cancer genomic studies identified RNF43 and ZNRF3,
as genes mutated in colon and liver cancer patients. However, their role
in liver disease has been unexplored. The research lab of Meritxell
Huch at the MPI-CBG, together with colleagues at the Gurdon Institute (Cambridge, UK) and at the University of Cambridge, has now investigated
the mechanisms by which alterations in these two genes can affect the
emergence of liver diseases.
Their study is published in the journal Nature Communications.
To pursue this goal, the researchers worked with mice as an animal model,
data from human individuals, human tissues, and liver organoid cultures,
which are 3D cellular microstructures made out of hepatocytes that
resemble liver in a dish. Germa'n Belenguer, first author of the study
and postdoctoral researcher in the group of Meritxell Huch, explains,
"With the organoid, we were able to grow hepatocytes mutated only in
these genes, and we saw that the loss of these activates a signal that regulates the metabolism of lipids. As a result, the fat metabolism
is no longer under control and lipids accumulate in the liver, which
leads in turn to a fatty liver. Another result of the activated signal
is that hepatocytes multiply uncontrollably. Both mechanisms combined facilitate the progression towards fatty liver disease and cancer." The scientists then compared the results from the experiments with patient
data in a publicly available dataset from the International Cancer Genome Consortium. They evaluated the prognosis of survival when the two genes
are mutated in liver cancer patients and found that patients with these
mutated genes show fatty liver disease and have a worse prognosis than
liver cancer patients with the two genes unmutated.
"Our findings can help identify individuals with a RNF43/ZNRF3 mutation
and therefore at risk of developing a fatty liver or liver cancer,"
says Meritxell Huch. She continues, "With the alarming increase in the consumption of fat and sugar worldwide, recognizing those individuals
already predisposed because of bearing those genetic mutations might
be important for the therapeutic intervention and management of the
disease, especially at very early stages or even before the disease is initiated. We will need more studies to further characterize the roles
of the two genes in human fatty liver disease, NASH, and human liver
cancer and to identify therapeutics that could help those patients
that are already intrinsically predisposed to develop the disease." ========================================================================== Story Source: Materials provided by Max_Planck_Institute_of_Molecular_Cell_Biology_and
Genetics_(MPI-CBG). Note: Content may be edited for style and length.
========================================================================== Journal Reference:
1. Germa'n Belenguer, Gianmarco Mastrogiovanni, Clare Pacini, Zoe
Hall, Anna
M. Dowbaj, Robert Arnes-Benito, Aleksandra Sljukic, Nicole
Prior, Sofia Kakava, Charles R. Bradshaw, Susan Davies,
Michele Vacca, Kourosh Saeb- Parsy, Bon-Kyoung Koo, Meritxell
Huch. RNF43/ZNRF3 loss predisposes to hepatocellular-carcinoma
by impairing liver regeneration and altering the liver lipid
metabolic ground-state. Nature Communications, 2022; 13 (1) DOI:
10.1038/s41467-021-27923-z ==========================================================================
Link to news story:
https://www.sciencedaily.com/releases/2022/01/220118104131.htm
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