Washington [US], Liver failure as a vital organ is becoming increasingly common due to fatty liver disease, often referred to as steatotic liver disease or SLD for short. Researchers have now found that a saturated fatty acid in blood vessels causes the synthesis of the signaling molecule SEMA3A, which closes the blood vessel 'windows'.
This makes it more difficult for fat to move from the liver to the adipose tissue. When SEMA3A is suppressed, the windows reopen and the amount of fat in the liver is reduced, researchers write in the journal Nature Cardiovascular Research.
The team of researchers from the Institute of Metabolic Physiology at Heinrich Heine University Düsseldorf (HHU), is working with the German Diabetes Center (DDZ) and other partners.In particular, 'metabolic dysfunction-associated SLD' (abbreviated MASLD) can develop due to adverse lifestyle factors such as high-energy diet and low exercise. It already affects about a third of people worldwide. Initially, MASLD has no pathological implications, but it can develop into liver inflammation. In the long run, this can lead to liver cirrhosis, liver failure or even liver cancer. There are no alternative procedures that can take over long-term liver function, such as dialysis for kidney failure.Affected people are at high risk and can only be cured by a liver transplant.
In addition, people with MASLD have an increased risk of developing type 2 diabetes or dying from cardiovascular diseases. Obesity favors MASLD, but not all obese people are affected. And vice versa, thin people can also develop this disease.
The molecular causes of the development of MASLD are not completely understood.A team of researchers from HHU, DDZ (Leibniz Center for Diabetes Research at HHU), Düsseldorf University Hospital (UKD) and Forschungszentrum Jülich (FZJ) have now discovered an important aspect that explains how MASLD develops.
The leading role is played by windows (Latin: fenestrae) in the endothelial cells of the blood vessel, through which the exchange of substances occurs between the liver cells and the blood. The liver uses these tiny windows to release excess fat particles into the adipose tissue through the bloodstream. The researchers found that these windows close by a mechanism in which the signaling molecule SEMA3A (semaphorin-3A) plays a central role. This molecule is produced in blood vessels when they are excessively exposed to the saturated fatty acid “palmitic acid.”Sydney Balkenholt of the Institute of Metabolic Physiology at HHU and DDZ, first author of the study published in Nature Cardiovascular Research, points to a discovery made by the team using scanning electron microscopy: "windows" in the smallest blood vessels. Mice with fatty liver and type 2 diabetes mellitus also had liver blockage.
Dr. Daniel Eberhard, the other first author, says: "We were also able to reverse the effect. By inhibiting the signaling molecule, we could depolarize the liver and thus restore its function."
Corresponding author Dr. Eckhard Lammert, professor and head of the Institute of Metabolic Physiology at HHU and the Institute of Vascular and Islet Cell Biology at the DDZ, hopes that these discoveries will also lead to a therapeutic approach for humans in the long term: "This early stage It may be possible to use the SEMA3A signaling molecule we identified to prevent MASLD and its consequences, however, we first need to investigate the processes in detail in humans.
This makes it more difficult for fat to move from the liver to the adipose tissue. When SEMA3A is suppressed, the windows reopen and the amount of fat in the liver is reduced, researchers write in the journal Nature Cardiovascular Research.
The team of researchers from the Institute of Metabolic Physiology at Heinrich Heine University Düsseldorf (HHU), is working with the German Diabetes Center (DDZ) and other partners.In particular, 'metabolic dysfunction-associated SLD' (abbreviated MASLD) can develop due to adverse lifestyle factors such as high-energy diet and low exercise. It already affects about a third of people worldwide. Initially, MASLD has no pathological implications, but it can develop into liver inflammation. In the long run, this can lead to liver cirrhosis, liver failure or even liver cancer. There are no alternative procedures that can take over long-term liver function, such as dialysis for kidney failure.Affected people are at high risk and can only be cured by a liver transplant.
In addition, people with MASLD have an increased risk of developing type 2 diabetes or dying from cardiovascular diseases. Obesity favors MASLD, but not all obese people are affected. And vice versa, thin people can also develop this disease.
The molecular causes of the development of MASLD are not completely understood.A team of researchers from HHU, DDZ (Leibniz Center for Diabetes Research at HHU), Düsseldorf University Hospital (UKD) and Forschungszentrum Jülich (FZJ) have now discovered an important aspect that explains how MASLD develops.
The leading role is played by windows (Latin: fenestrae) in the endothelial cells of the blood vessel, through which the exchange of substances occurs between the liver cells and the blood. The liver uses these tiny windows to release excess fat particles into the adipose tissue through the bloodstream. The researchers found that these windows close by a mechanism in which the signaling molecule SEMA3A (semaphorin-3A) plays a central role. This molecule is produced in blood vessels when they are excessively exposed to the saturated fatty acid “palmitic acid.”Sydney Balkenholt of the Institute of Metabolic Physiology at HHU and DDZ, first author of the study published in Nature Cardiovascular Research, points to a discovery made by the team using scanning electron microscopy: "windows" in the smallest blood vessels. Mice with fatty liver and type 2 diabetes mellitus also had liver blockage.
Dr. Daniel Eberhard, the other first author, says: "We were also able to reverse the effect. By inhibiting the signaling molecule, we could depolarize the liver and thus restore its function."
Corresponding author Dr. Eckhard Lammert, professor and head of the Institute of Metabolic Physiology at HHU and the Institute of Vascular and Islet Cell Biology at the DDZ, hopes that these discoveries will also lead to a therapeutic approach for humans in the long term: "This early stage It may be possible to use the SEMA3A signaling molecule we identified to prevent MASLD and its consequences, however, we first need to investigate the processes in detail in humans.
