Fatty liver disease, or steatotic liver disease (SLD), is becoming increasingly prevalent and can lead to failure of the liver as a vital organ. A team of researchers from Heinrich Heine University Düsseldorf, in collaboration with the German Diabetes Centre and other partners, has discovered that a saturated fatty acid in blood vessels leads to the production of the signalling molecule SEMA3A, which closes the windows in the blood vessels, hindering the transport of fat from the liver to adipose tissue. Inhibiting SEMA3A can open these windows again, reducing fat in the liver.
Metabolic dysfunction-associated SLD (MASLD) can develop due to lifestyle factors such as high-energy diets and lack of exercise, affecting a significant portion of the global population. MASLD can progress to liver inflammation, cirrhosis, liver failure, and even liver cancer over time. Unlike kidney failure, there is currently no long-term substitute procedure for liver function, making liver transplant the only cure for those at high risk of liver disease.
People with MASLD have an increased risk of developing type 2 diabetes mellitus or dying from cardiovascular diseases, and obesity is a key risk factor for MASLD. However, not all obese individuals develop the disease, and conversely, even slim people can be affected. The molecular mechanisms underlying MASLD development are not fully understood, but researchers have identified the role of windows in endothelial cells of blood vessels in facilitating the exchange of substances between liver cells and blood.
The researchers found that SEMA3A, produced in blood vessels exposed to the saturated fatty acid palmitic acid, plays a central role in closing these windows and preventing the release of excess fat particles from the liver to adipose tissue through the bloodstream. In mouse models with fatty liver and type 2 diabetes mellitus, the closure of these windows was observed, but inhibiting SEMA3A effectively reversed this effect, leading to improved liver function by reducing fat accumulation.
The study’s first authors, Sydney Balkenhol and Dr. Daniel Eberhard, point to the potential for targeting SEMA3A as a therapeutic approach for preventing MASLD and its consequences at an early stage. Dr. Eckhard Lammert, the corresponding author and Professor at Heinrich Heine University Düsseldorf, is optimistic that further research on these processes in humans may lead to the development of new treatment strategies for SLD. By understanding the molecular mechanisms involved in the development of MASLD, researchers hope to find ways to intervene and prevent the progression of liver disease in affected individuals.
