Additional genetic cause for non-alcoholic fatty liver disease discovered

May 19, 2020

In Germany about 18 million people suffer from non-alcoholic fatty liver. The causes of this disease are manifold and include environmental as well as genetic factors. DZD researchers have now discovered new genes that play a role in the development of fatty liver. In humans and mice, respectively, the genes IRGM, Ifgga2 and Ifgga4 are responsible for the production of regulatory proteins of the family of immunity-related GTPases which counteract fat accumulation in the liver. However, a genetic variation leads to the formation of fewer of these proteins. The results have now 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 Europe about 20-30 percent of the population are affected. NAFLD is often associated with other diseases such as 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, high-sugar diet and lack of exercise, a genetic predisposition is also responsible for the development of this liver disease. However, for this complex disease not only one gene butrather the interactions of different genes and epigenetic * factors are responsible. Researchers have now discovered a new family of genes that play an important role in preventing fatty liver development. In humans and mice, these genes 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. The study, which has now been published in the Journal of Hepatology, was carried out by a team of researchers of the German Institute of Human Nutrition Potsdam-Rehbrücke (DIfE), the German Diabetes Center (DDZ) and Helmholtz Zentrum München - all partners of the German Center for Diabetes Research (DZD).

New genes identified


Using molecular markers and statistical methods - quantitative trait locus (QTL) analysis - genes that cause complex human diseases can be identified in mouse strains. For example, the research team discovered a region on mouse chromosome 18 that was associated with altered amounts of fat in the liver. If the genes Ifgga2 and Ifgga4 are expressed, proteins of the family of immunity-related GTPases are formed - in the mouse the proteins IFGGA2 and IFGGA4 and in humans the protein IRGM. These proteins increase a certain form of fat degradation and thus counteract the development of fatty liver.

The reason for a lower expression in mice with a fatty liver is a small genetic variation. "Due to the loss of only a single base in a gene sequence, which increases the expression 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," 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). 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-fold.

Proteins increase specific degradation of fat in the liver (lipophagy)


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," explained Dr. Wenke Jonas, who co-directed the study together with Professor Schürmann. Autophagy is a type of cellular disposal and recycling process through which the cell's own components are degraded. The researchers have observed that after the uptake of fatty acids in liver cells, the immunity-related GTPases migrate to the lipid droplets. There they bind to an enzyme involved in fat degradation (adipocyte triglyceride lipase, ATGL) and ensure that a central protein of autophagy (LC3B) binds to the fat droplet. Due to the autophagy of lipid droplets, the amount of fat is reduced and thus the development of fatty liver is prevented.

The researchers were also able to show that the immunity-related GTPases affect the amount of fat in the liver in the following two studies: If they inhibited the synthesis of the proteins, mice stored more fat in the liver cells. If, on the other hand, the production of the proteins in liver cells was increased, the cells stored considerably less fat.

"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 Schürmann. "Our next goal is to clarify which measures - such as diets or certain drugs - can increase the amount of immunity-related GTPases in order to reduce fat storage in the liver."

* Epigenetics investigates those properties of genes that are not revealed by the DNA sequence itself, but by their expression. Epigenetic information is mediated by methyl groups or other biomolecules which, like chemical locks, deny or release access to certain DNA sequences and thus control their activation. Which epigenetic code is established in a person and whether it changes in the course of life is determined not only by the body's own signal substances but also by eating habits and other aspects of lifestyle.
-end-
Original Publication: Schwerbel, K. et al: Immunity-related GTPase induces lipophagy to prevent excess hepatic lipid accumulation. Journal of Hepatology (2020); DOI: https://doi.org/10.1016/j.jhep.2020.04.031

Deutsches Zentrum fuer Diabetesforschung DZD

Related Diabetes Articles from Brightsurf:

New diabetes medication reduced heart event risk in those with diabetes and kidney disease
Sotagliflozin - a type of medication known as an SGLT2 inhibitor primarily prescribed for Type 2 diabetes - reduces the risk of adverse cardiovascular events for patients with diabetes and kidney disease.

Diabetes drug boosts survival in patients with type 2 diabetes and COVID-19 pneumonia
Sitagliptin, a drug to lower blood sugar in type 2 diabetes, also improves survival in diabetic patients hospitalized with COVID-19, suggests a multicenter observational study in Italy.

Making sense of diabetes
Throughout her 38-year nursing career, Laurel Despins has progressed from a bedside nurse to a clinical nurse specialist and has worked in medical, surgical and cardiac intensive care units.

Helping teens with type 1 diabetes improve diabetes control with MyDiaText
Adolescence is a difficult period of development, made more complex for those with Type 1 diabetes mellitus (T1DM).

Diabetes-in-a-dish model uncovers new insights into the cause of type 2 diabetes
Researchers have developed a novel 'disease-in-a-dish' model to study the basic molecular factors that lead to the development of type 2 diabetes, uncovering the potential existence of major signaling defects both inside and outside of the classical insulin signaling cascade, and providing new perspectives on the mechanisms behind insulin resistance in type 2 diabetes and possibly opportunities for the development of novel therapeutics for the disease.

Tele-diabetes to manage new-onset diabetes during COVID-19 pandemic
Two new case studies highlight the use of tele-diabetes to manage new-onset type 1 diabetes in an adult and an infant during the COVID-19 pandemic.

Genetic profile may predict type 2 diabetes risk among women with gestational diabetes
Women who go on to develop type 2 diabetes after having gestational, or pregnancy-related, diabetes are more likely to have particular genetic profiles, suggests an analysis by researchers at the National Institutes of Health and other institutions.

Maternal gestational diabetes linked to diabetes in children
Children and youth of mothers who had gestational diabetes during pregnancy are at increased risk of diabetes themselves, according to new research published in CMAJ (Canadian Medical Association Journal).

Two diabetes medications don't slow progression of type 2 diabetes in youth
In youth with impaired glucose tolerance or recent-onset type 2 diabetes, neither initial treatment with long-acting insulin followed by the drug metformin, nor metformin alone preserved the body's ability to make insulin, according to results published online June 25 in Diabetes Care.

People with diabetes visit the dentist less frequently despite link between diabetes, oral health
Adults with diabetes are less likely to visit the dentist than people with prediabetes or without diabetes, finds a new study led by researchers at NYU Rory Meyers College of Nursing and East Carolina University's Brody School of Medicine.

Read More: Diabetes News and Diabetes Current Events
Brightsurf.com is a participant in the Amazon Services LLC Associates Program, an affiliate advertising program designed to provide a means for sites to earn advertising fees by advertising and linking to Amazon.com.