Lily-livered liver cells
The liver is vital for whole body metabolism and detoxification. For this job liver cells must internalize nutrients or get rid of substances and send or receive signals. Certain genes regulate these processes – and a loss of these genes may trigger serious diseases, as for instance the induction of high blood cholesterol levels.
Researchers at the MPI-CBG were interested in learning how cells organise the complex network of hundreds of endosomes in the liver, which are responsible to distribute or get rid of nutrients and signalling molecules in the cell. The team focused on one major player, the gene Rab5.
First, researchers developed a mathematical model to predict the dependency of endosome formation on Rab5. The theory was then verified in practice by using state-of-the-art RNAi technology that has been developed to silence genes for therapeutics: The three Rab5 genes were knocked down together in the liver of mice.
The consequences were striking and devastating: Electron microscopy images confirmed that depletions of Rab5 led to a loss of 80% of the necessary endosomes – the metabolism of the cell collapsed. Animals suffered from a number of severe metabolic defects such as intracellular glycogen and fat droplets accumulation and their livers were severely affected leading to high blood cholesterol.
The experiments show that the Rab5 indeed acts as a crucial endosome organizer and a potential regulator of liver physiology. Therefore, these data and technologies can help to discover new genes regulating glucose and lipid metabolism and to develop new therapeutic strategies for human diseases.
The results are also an important contribution to the project "Virtual Liver" of the German Federal Ministry of Education and Research (www.virtual-liver.de): The aim of this project is to understand the liver as an organ by developing a dynamic model that describes its functions and complexity as a basis to develop novel clinical applications.
Anja Zeigerer, Jerome Gilleron, Roman L. Bogorad, Giovanni Marsico, Hidenori Nonaka, Sarah Seifert, Hila Epstein-Barash, Satya Kuchimanchi, Chang Geng Peng, Vera M. Ruda, Perla Del Conte-Zerial, Jan G. Hengstler, Yannis Kalaidzidis, Victor Koteliansky and Marino Zerial:
Rab5 is necessary for the biogenesis of the endolysosomal system in vivo
Nature, 24 May 2012