The volume of animal cells needs to be tightly controlled, especially upon osmotic challenges but also during cell growth, migration and death. Cellular volume changes are also believed to have a role in cell signaling, in particular for insulin secretion by pancreatic β-cells and liver metabolism. Indeed, several studies established that anabolic processes (e.g. induced by insulin) are associated with swelling and catabolic processes (e.g. induced by glucagon) with shrinkage of hepatocytes, the main epithelial cells in the liver. However, the causal relationship between changes in hepatocyte volume and liver metabolism is largely obscure. Under physiological conditions, postprandial uptake of nutrients such as amino acids would increase hepatic metabolism after induction of osmotic cell swelling. The question of how hepatocyte swelling is sensed and transduced to regulate metabolism also remains unanswered.
As major player in cell volume regulation, the Volume-Regulated Anion Channel VRAC may influence liver metabolism by controlling hepatocyte volume. In parallel with another group, VRAC has been identified by the host laboratory as LRRC8 heteromers with LRRC8A being the obligatory subunit. With the recent identification of LRRC8 subunits as VRAC components, it is now possible to rigorously assess physiological roles of VRAC in the liver and its metabolic pathways.
Because the liver is a key organ controlling lipid and carbohydrate metabolism, dysregulations of hepatic signaling pathways can lead to metabolic diseases. If some cascades are identified as regulated by VRAC, this channel may therefore represent an interesting therapeutic target for the treatment of metabolic diseases such as the non-alcoholic steatosis hepatitis (NASH).
The overarching aim of this study was thus to (i) investigate the role of VRAC in liver function and in particular, (ii) to determine whether it is involved in the coupling of cell swelling with metabolism in hepatocytes.
