Non-alcoholic fatty liver disease (NAFLD) is an extremely prevalent hepatic pathology that affects about one quarter of adults in the developed world. This disease spectrum includes diff erent conditions ranging from simple steatosis, to non-alcoholic steatohepatitis (NASH), fibrosis and cirrhosis. Insulin resistance and obesity are two well-established pathogenic factors associated to NAFLD, and in fact NAFLD is a very common condition among patients with type 2 diabetes. G protein-coupled receptor kinase 2 (GRK2), classically known as a regulator of G protein-coupled receptors, has been described to play a relevant role in the development of IR and obesity in vivo. However, the eff ect of GRK2 in the development of NASH had not been addressed so far. Here we investigate the contribution of GRK2 to NASH in mice subjected to a methionine and choline-deficient diet (MCD), a well-stablished model of NASH that is independent of fat mass accretion. [Results]: We analyzed a variety of metabolic parameters in WT and GRK2+/- mice fed a MCD diet for four weeks. MCD induced similar alterations and a comparable elevation in plasma transaminase activity in WT and GRK2+/- mice. However, steatosis and other negative effects of this diet in the liver were partially alleviated in GRK2 +/- animals. For instance, the increase in hepatic triglyceride accumulation? and in the liver to body weight ratio induced by MCD were significantly lower in GRK2+/- mice. Furthermore, pathophysiological examination revealed signifi cantly lower NAFLD activity score (NAS) in GRK2+/- mice which were protected from overt NASH. GRK2+/- mice also presented protection from some deleterious effects of the MCD in the liver, such as reduced expression of markers of endoplasmic reticulum stress and inflammation. Moreover, GRK2+/- mice retained certain hepatic protective mechanisms after the MCD as revealed using markers of autophagy and mitochondrial fusion processes. We also found that MCD feeding induced an increase in GRK2 protein levels in WT but not in GRK2+/- livers, similar to what is observed in hepatic tissue of mice fed with a high fat diet. Interestingly, a similar increase in GRK2 protein was also observed in human hepatic samples of NAFLD patients by immunohistochemistry. In the same line, we found that Huh7 cells overexpressing GRK2 accumulated more lipids when exposed to palmitic acid compared to controls. [Conclusion]: Our results uncover a role for GRK2 in the regulation of hepatic lipid metabolism, and provide a proof of concept that reducing the levels of this kinase can impair the development of NASH.

Resumen del póster presentado al 1st Joint Meeting of the French-Portuguese-Spanish Biochemical and Molecular Biology Societies y al XL Spanish Society of Biochemistry and Molecular Biology (SEBBM) Congress, celebrado en Barcelona (España) del 23 al 26 de octubre de 2017.

Peer reviewed