Additional Genetic Cause for NAFLD Discovered

Immunity-related GTPase induces lipophagy to prevent excess hepatic lipid accumulation. Journal of Hepatology, 2020

© DIfE

The cause of non-alcoholic fatty liver disease (NAFLD) is multifactorial, including genetic and environmental factors. Currently, only a few genetic variants explain the heritability of the disease. DZD researchers have now discovered new genes that play a role in the development of fatty liver. The results have been published in the Journal of Hepatology.

Non-alcoholic fatty liver disease (NAFLD) is the leading cause of chronic liver disease in Europe and the United States. In addition to an unhealthy lifestyle with a high-fat, high-sugar diet and lack of exercise, a genetic predisposition is also responsible for the development of this liver disease.

Using molecular markers and statistical methods – quantitative trait locus (QTL) analysis – genes that cause complex human diseases can be identified in mouse strains. Researchers have now discovered a new family of genes that play an important role in preventing fatty liver development. In humans and mice, the genes IRGM, Ifgga2 and Ifgga4 produce regulatory proteins from the family of immunity-related GTPases that counteract fat accumulation in the liver. However, if there is a genetic modification, fewer proteins are formed. Studies show that the liver of patients with NAFLD and mice with fatty liver have significantly lower amounts of these proteins.

Functional studies have shown that an overproduction of immunity-related GTPases in liver cells or in the liver of mice, significantly reduced their fat content. The reason for this is the induction of a particular form of autophagy that is specific for the degradation of fats and is therefore called lipophagy.

“Our work has identified further important genes that cause fatty liver disease. The study results also deepen our understanding of which cellular processes have to be stimulated to counteract fatty liver development,” said Professor Annette Schürmann, head of the Department of Experimental Diabetology at the German Institute of Human Nutrition Potsdam-Rehbrücke (DIfE) and spokesperson for the German Center for Diabetes Research (DZD).

Original publication:
Schwerbel, K. et al: Immunity-related GTPase induces lipophagy to prevent excess hepatic lipid accumulation. Journal of Hepatology (2020); DOI: