Researchers have identified a new approach to combat fatty liver disease, also known as steatotic liver disease (SLD). A team from Heinrich Heine University Düsseldorf (HHU) and the German Diabetes Centre (DDZ) has discovered that a saturated fatty acid in blood vessels triggers the production of the signalling molecule SEMA3A, which closes the “windows” in blood vessel endothelial cells. This closure prevents fat from moving from the liver to adipose tissue, exacerbating fatty liver disease.
The study, published in Nature Cardiovascular Research, found that by inhibiting SEMA3A, these windows could be reopened, allowing fat to leave the liver and thereby reducing liver fat content. This finding is particularly relevant for metabolic dysfunction-associated SLD (MASLD), which can arise from poor lifestyle choices like high-calorie diets and lack of exercise. MASLD affects about one-third of the global population and can lead to serious conditions such as liver inflammation, cirrhosis, liver failure, and liver cancer.
The researchers emphasized that no long-term substitute exists for liver function, making liver transplants the only cure for severe cases. Furthermore, MASLD increases the risk of type 2 diabetes and cardiovascular diseases. Notably, while obesity is a common risk factor, MASLD can also affect non-obese individuals.
The research team, including members from Düsseldorf University Hospital (UKD) and Forschungszentrum Jülich (FZJ), discovered that SEMA3A is produced in blood vessels when exposed to palmitic acid, a saturated fatty acid. This molecule’s role in closing endothelial windows was confirmed using scanning electron microscopy in mice models with fatty liver and type 2 diabetes.
Sydney Balkenhol from HHU and DDZ, the study’s first author, highlighted the team’s use of scanning electron microscopy to observe these closed windows. Co-author Dr. Daniel Eberhard noted that inhibiting SEMA3A successfully reversed this effect, leading to liver defatting and functional improvement.
Dr Eckhard Lammert, the corresponding author and head of the Institute of Metabolic Physiology at HHU, expressed hope that this discovery could eventually lead to human therapies. He stressed the need for further research to explore the applicability of SEMA3A inhibition in preventing and treating MASLD in humans.
