New potential therapeutic targets for non-alcoholic fatty liver disease discovered

Rab24 is a small Rab GTPase that has been shown to be a new regulator of mitochondrial activity and plasticity. The research group led by diabetes scientist Anja Zeigerer was able to demonstrate that Rab24 is highly up-regulated in obese NAFLD patients in the liver. In a next step, she was able to show that reducing Rab24 in diet-related obesity models greatly improves liver steatosis and glucose tolerance. This indicates an overall improvement in the health of the liver and organism. Rab24 is therefore a new potential therapeutic target for the treatment of NAFLD.

"The prevalence of type 2 diabetes and its comorbidities, such as NAFLD, is increasing dramatically. Worldwide, 1.8 billion people are affected by NAFLD and there are no approved treatment options on the market. Therefore, it is particularly important to explore new intracellular targets such as Rab24 for possible therapeutic options, "says Anja Zeigerer.

Less Rab24, better function of the mitochondria

In the search for new therapeutic targets, Anja Zeigerer's group focused on components of the intracellular transport system machinery as well as organelle integrity. The group analyzed novel functions of membrane transport candidates in the control of liver glucose and lipid metabolism. The team discovered Rab24 as a new regulator of the dynamics of mitochondria and energy metabolism.

The dynamics of mitochondria is strongly regulated by their plasticity and turnover, which in turn is controlled by the availability of nutrients. Fasting inhibits mitochondrial division and induces highly interconnected and functional mitochondria that can utilize all available substrates for energy production. In metabolic diseases with a constant supply of food, the mitochondria are fragmented, which greatly reduces their activity and breathability.

The group found that Rab24 affects the machinery responsible for mitochondrial division, and that the mitochondria are better connected by the reduction of Rab24 and therefore more functional. Interestingly, the group noted an accumulation of Rab24 in the liver of overweight patients with NAFLD. This accumulation could lead to an increased number of fragmented mitochondria and increased energy storage in these patients. The data obtained from the reduction of Rab24 in diet-related obesity models offers the prospect of therapeutic use of cellular regulators - such as Rab24 for NAFLD. In addition, the results emphasize a functional relationship between intracellular membrane transport and systemic metabolic dysfunction.

"In a next step, we want to investigate Rab24 as a potential therapeutic target for NAFLD. Our goal is to find inhibitors that inhibit the effect of Rab24 on mitochondrial division and to test whether such inhibitors can mimic the observed improvements in this study, "said Susanne Seitz, lead author of the study.

Strong internal institutional cooperation and financing

The study was conducted under the supervision of Prof. Stephan Herzig, Director of the Institute for Diabetes and Cancer. It benefited greatly from the infrastructure of the Helmholtz Zentrum München: Inspired by a collaboration with the German Mouse Clinic and Prof. Martin Hrabe de Angelis, Institute for Experimental Genetics; supported by the Leipzig satellite institute HI-MAG in collaboration with Prof. Matthias Blüher, who provided valuable human samples for expression analysis; and funded by the German Research Foundation (DFG), the European Diabetes Foundation (EFSD) and the German Center for Diabetes Research (DZD).

Original Publication:
Anja Zeigerer et al., 2019: Hepatic Rab24 controls blood glucose homeostasis via improving mitochondrial plasticity. Nature Metabolism, DOI: 10.1038 / s42255-019-0124-x

As the German Research Center for Health and Environment, Helmholtz Zentrum München pursues the goal of developing personalized medicine for the diagnosis, treatment and prevention of widespread widespread diseases such as diabetes mellitus, allergies and lung diseases. It examines the interaction of genetics, environmental factors and lifestyle. The headquarters of the center is located in Neuherberg in the north of Munich. The Helmholtz Zentrum München employs around 2,500 people and is a member of the Helmholtz Association, which includes 19 scientific-technical and medical-biological research centers with around 37,000 employees.
The Institute for Diabetes and Cancer (IDC) is a member of the Helmholtz Diabetes Center (HDC) at Helmholtz Zentrum München