A MedUni Vienna study has identified a new approach to the drug treatment of metabolic liver diseases. In an experimental study, pharmacological inhibition of an enzyme that plays a central role in fat metabolism promoted liver health as well as reduced liver fat, inflammation and fibrotic remodeling (connective tissue scarring). The results were published in the Journal of Hepatology.

Metabolic dysfunction-associated steatotic liver disease (MASLD, formerly known as non-alcoholic fatty liver disease [NAFLD]) is the most common and rapidly increasing cause of chronic liver disease worldwide, which can lead to liver cirrhosis and liver cancer via the development of steatohepatitis (MASH, formerly NASH) and thus represents a significant challenge for the health care system. Despite lifestyle modification (diet and exercise) and the recent approval of new drugs, the development of targeted therapeutic approaches remains an urgent concern.

The current study, first authored by Emmanuel Dauda Dixon and led by Michael Trauner at MedUni Vienna's Division of Gastroenterology and Hepatology (Department of Medicine III), focused on blocking ATGL (adipose triglyceride lipase). This enzyme plays a central role in lipid metabolism by mediating the first step in the intracellular breakdown of stored triglycerides. The effect of the ATGL-specific enzyme inhibitor atglistatin (ATGLi) was investigated in preclinical models.

In mice that developed MASH as a result of a high-fat diet and chemical intervention, the use of ATGLi significantly improved liver health, reduced liver fat and inflammation and decreased fibrotic remodeling. These effects were achieved by interfering with the PPARα signaling pathway and promoting the synthesis of hydrophilic bile acids.

"A remarkable breakthrough is the demonstration that the inhibition of ATGL also leads to similar positive effects in human cell models," explains first author Dixon. "With the specific inhibitor, we were able to show that mechanisms similar to those of atglistatin can also be transferred to human ATGL. This is a decisive step towards clinical application."

Study leader Trauner emphasizes, "Our investigations show that the inhibition of ATGL not only acts locally in the liver but surprisingly also has a positive effect on the composition of bile acids and fat absorption in the intestine. This opens novel perspectives for the treatment of MASLD and MASH. Our work creates the basis for the development of new pharmacological approaches that specifically target the pathophysiology of the disease.

"With these findings, MedUni Vienna is making a significant contribution to the development of innovative treatment strategies for liver diseases that affect millions of people worldwide."

MASLD -- one of the main causes of liver cancer

The incidence of metabolic dysfunction-associated steatotic liver disease (MASLD), formerly known as non-alcoholic fatty liver disease (NAFLD), is rising sharply worldwide and is a burden on public health. The main causes are unhealthy lifestyle habits and overeating, and MASLD is also a major consequence of obesity and diabetes.

Currently, one-third of the population is already affected by MASLD, and the trend is rising. Currently, moderate weight reduction and the drug Resmetirom are considered effective measures, but new pharmacological approaches are urgently needed. Understanding the underlying mechanisms is essential for the development of targeted therapies.