New approach against hepatic steatosis: molecular pathway identified

Fatty liver disease (FLD) increasingly leads to failure of the liver as a vital organ. A team led by researchers from the Institute of Metabolic Physiology at the Heinrich Heine University Düsseldorf (HHU) in collaboration with the German Diabetes Center (DDZ) and other partners has discovered that a saturated fatty acid in blood vessels leads to the production of the signaling molecule SEMA3A, which closes the “windows” in the blood vessels. This interferes with the transport of fats from the liver to adipose tissue.

In the magazine Nature Cardiovascular Researchresearchers report that the windows open again and fat in the liver decreases when SEMA3A is inhibited.

In particular, SLD associated with metabolic dysfunction (MASLD) may develop due to adverse lifestyle factors, such as an energy-dense diet and lack of exercise. It already affects around a third of the world's population.

Initially, MASLD has no pathological effects, but it can progress to liver inflammation. In the long term, this can lead to liver cirrhosis, liver failure, and even liver cancer. There is no replacement procedure that can ensure long-term liver function, such as dialysis in cases of kidney failure.

Affected people are at high risk and can only be cured by a liver transplant. Additionally, people with MASLD have an increased risk of developing type 2 diabetes mellitus or dying from cardiovascular disease. Obesity promotes MASLD, but not all obese people are affected. And conversely, thin people can also develop the disease.

The molecular causes of the development of MASLD are not fully understood. A team of researchers from HHU, DDZ (Leibniz Center for Diabetes Research at HHU), University Hospital Düsseldorf (UKD) and Forschungszentrum Jülich (FZJ) have discovered an important aspect that explains the development of MASLD.

The main role is played by windows (Latin: fenestrae) in the endothelial cells of blood vessels, through which substances are exchanged between liver cells and blood. The liver uses these tiny windows to release excess fat particles into adipose tissue via the bloodstream.

Researchers discovered that these windows are closed by a mechanism in which the signaling molecule SEMA3A (semaphorin-3A) plays the central role. This molecule is produced in blood vessels when they are too exposed to the saturated fatty acid “palmitic acid”.

Sydney Balkenhol of the Institute of Metabolic Physiology at HHU and DDZ, first author of the study, highlights a discovery the team made using scanning electron microscopy: “windows” in the smallest blood vessels of the liver were also closed in mice. with fatty liver and type 2 diabetes mellitus.

Dr. Daniel Eberhard, the other first author, adds: “We were also able to reverse the effect. By inhibiting the signaling molecule, we could defat the liver and thus improve its function again.”

Corresponding author Dr. Eckhard Lammert, professor and director of the Institute for Metabolic Physiology at HHU and the Institute for Vascular Cell and Islet Biology at DDZ, hopes that the findings will also lead to a therapeutic approach for humans in the long term.

“It might be possible to use the SEMA3A signaling molecule we identified to prevent MASLD and its consequences at an early stage. However, we first need to study the processes in humans in detail.”