Non-alcoholic fatty liver: Another genetic cause discovered
Although many people think of alcohol as “fatty liver” quickly, there are completely different causes for fatty liver disease. Researchers have now discovered another genetic trigger for non-alcoholic fatty liver (NAFL).
According to the German Liver Foundation, around a third of adults have an enlarged liver due to fat storage - and the number is constantly increasing. A distinction is made between non-alcoholic fatty liver (NAFL) and alcoholic fatty liver (AFL). In addition to improper nutrition, lack of exercise and obesity, high alcohol consumption or diabetes, the causes that mostly lead to fatty liver in combinations. Researchers have now discovered another cause.
About 18 million people in Germany are affected
According to a recent release from the German Center for Diabetes Research (DZD), around 18 million people in Germany suffer from non-alcoholic fatty liver. The causes of this disease are diverse and include environmental as well as genetic factors.
Scientists at the DZD have now discovered new genes that play a role in the development of fatty liver.
The genes IRGM, Ifgga2 and Ifgga4 ensure the production of regulatory proteins of the family of immune-associated GTPases in humans and mice, respectively, which counteract fat accumulation in the liver. However, a genetic change means that fewer of these proteins are formed.
The results were recently published in the Journal of Hepatology.
Unhealthy lifestyle and genetic predisposition
According to the DZD, non-alcoholic fatty liver disease (NAFLD) is the most common cause of chronic liver disease in Europe and the United States. In Europe, around 20-30 percent of the population suffer from it.
NAFLD is often associated with other diseases such as obesity (obesity), type 2 diabetes, high blood pressure (arterial hypertension) and a fat metabolism disorder (dyslipidemia).
In addition to an unhealthy lifestyle with a high-fat and sugar-rich diet and a lack of exercise, a genetic predisposition is also responsible for the development of this liver disease.
NAFLD is a complex disease for which there is not just one disease gene. The interactions of different genes and epigenetic factors play a role. Researchers have now discovered a new gene family that plays an important role in preventing fatty liver development.
In humans and also in mice, these genes produce regulatory proteins from the family of immune-associated GTPases that counteract fat accumulation in the liver.
However, if there is a genetic change, fewer proteins are formed. Studies show that the liver of patients with NAFLD and mice with fatty liver has significantly lower amounts of these proteins.
The study was carried out by a research team from the German Institute for Nutritional Research Potsdam-Rehbrücke (DIfE), the German Diabetes Center (DDZ) and the Helmholtz Center Munich - all partners of the DZD.
New genes identified
According to the information, molecular markers and statistical methods (QTL analysis, quantitative trait locus) can be used to identify genes in mouse strains that cause complex human diseases.
The research team discovered an area on mouse chromosome 18 that was linked to changes in the amount of fat in the liver. When the genes Ifgga2 and Ifgga4 are read, proteins of the family of immune-associated GTPases are formed - in the mouse the protein IFGGA2 and IFGGA4 and in the human being the protein IRGM.
According to experts, these proteins increase a certain form of fat loss and thus counteract the development of fatty liver.
In humans, however, even in mice with a fatty liver, the genes are read far less. The reason for this is a small genetic change in mice.
"Due to the loss of only one base in a gene sequence, which increases the reading of a certain gene, the two related proteins IFGGA2 and IFGGA4 are hardly produced in liver cells of mice that are susceptible to fatty liver," explains Professor Annette Schürmann, head of the Department of Experimental Diabetology at DIfE and spokeswoman for the DZD.
Patients with NAFLD also have significantly lower amounts of the corresponding protein (IRGM). As a result, the fat content in the liver can increase three to four times.
Researchers want to find out how diets or medication can help
According to the communication, functional studies have shown that overproduction of the immune-associated GTPases in liver cells or in the liver of the mouse significantly reduced their fat content.
"The reason for this is the induction of a special form of autophagy, which is specific for the breakdown of fats and is therefore called lipophagy," explains Dr. Wenke Jonas, who led the study together with Prof. Schürmann.
According to the experts, autophagy is a kind of cellular disposal and recycling process through which the cell's own components are broken down.
The researchers observed that after fatty acids were taken up in liver cells, the immune-associated GTPases migrate to the fat drops, bind there to an enzyme for fat loss (adipocyte triglyceride lipase) and ensure that a central protein of autophagy (LC3B) is attached binds the fat drop.
The autophagy of lipid droplets reduces the amount of fats and prevents the formation of fatty liver.
The scientists were also able to show that the immune-associated GTPases influence the amount of fat in the liver by means of the following two studies: If they inhibited the synthesis of the proteins, mice stored more fat in the liver cells. However, if the production of proteins in liver cells was increased, they stored significantly less fat.
“Our work has identified other important genes that cause fatty liver disease. The study results also deepen our understanding of which cellular processes need to be stimulated to counteract fatty liver, ”said Schürmann.
"Our next goal is to clarify which measures - such as diets or certain medications - can increase the amount of immune-associated GTPases in order to reduce fat storage in the liver." (Ad)
Author and source information
This text corresponds to the specifications of the medical literature, medical guidelines and current studies and has been checked by medical doctors.
- German Center for Diabetes Research (DZD): Another genetic cause of non-alcoholic fatty liver discovered, (accessed: May 19, 2020), German Center for Diabetes Research (DZD)
- Schwerbel, K. et al: Immunity-related GTPase induces lipophagy to prevent excess hepatic lipid accumulation; in: Journal of Hepatology, (published: 04.05.2020), Journal of Hepatology
- German Liver Foundation: Inflammation of fatty liver (steatohepatitis) - most common liver disease in Germany, (accessed: May 19, 2020), German Liver Foundation