Targeting PNPLA3 activity to elucidate its role in MASLD

Liver steatosis when the liver becomes fatty: Liver steatosis, also known as fatty liver disease, is one of the most common liver diseases worldwide. It is caused by excessive fat accumulation in liver cells and is frequently associated with obesity, type 2 diabetes mellitus or excessive alcohol consumption. However, genetic factors also play a decisive role in the development and progression of this disease. Clinical significance of liver steatosis: In its early stages, liver steatosis does not cause any symptoms. However, if left untreated, it may progress to steatohepatitis, liver fibrosis and cirrhosis. In some cases, hepatocellular carcinoma (liver cancer) may also develop. Given the growing number of people affected, liver steatosis is an increasing global health problem. PNPLA3 a highly relevant genetic risk factor: The key genetic risk factor for the development and progression of liver steatosis is a variant in the PNPLA3 gene. This variant is found in approximately 20% of the population and is linked to an increased risk for liver steatosis, independent of classical risk factors like alcohol consumption or obesity. Carriers often exhibit a more severe disease course, highlighting PNPLA3 as both a valuable biomarker and a promising target for personalized therapeutic approaches. Despite its clinical relevance, the exact biological function of PNPLA3 and its variant in disease development has not yet been conclusively clarified. FWF-ASTRA Award goes to the Medical University of Graz: As part of the FWF-ASTRA Award, a multidisciplinary team of biochemists, medicinal chemists and clinical hepatologists will develop new chemical tools to elucidate the function of PNPLA3 in human model systems. Insights into how PNPLA3 influences development and progression of fatty liver disease could help open up new avenues for its prevention and treatment.