G protein-coupled receptor kinase 2 plays a role in the development of non-alcoholic steatohepatitis

Abstract

[Introduction]: Insulin resistance (IR) and obesity are major health problems and important risk factors for the development of non-alcoholic fatty liver disease, a disease spectrum that may include hepatic steatosis, non-alcoholic steatohepatitis (NASH), fibrosis, and cirrhosis. G protein-coupled receptor kinase 2 (GRK2), first identified as a regulator of G protein-coupled receptors (GPCRs), has been described to play a relevant role in the development of IR and obesity in vivo. However, the effect of GRK2 in the development of NASH had not been addressed so far. Since the deletion of GRK2 prevents excessive body weight gain, we fed WT and GRK2 global hemizygous mice (GRK2+/-) with a methionine and choline-deficient diet (MCD), a well stablished model of NASH that is independent of fat mass accretion. [Results]: Even though the MCD diet induced similar metabolic alterations and a comparable elevation in plasma transaminase activity in WT and GRK2+/- mice, other negative effects of the MCD were partially alleviated in GRK2 +/- animals. The increase in hepatic triglyceride content caused by this diet was significantly lower in GRK2+/- mice and, interestingly, MCD feeding induced an increase in GRK2 protein levels in WT but not in GRK2+/- livers. Moreover, GRK2+/- mice presented protection from some deleterious effects of MCD in the liver as indicated by reduced markers of endoplasmic reticulum stress, and conversely maintained some hepatic protective mechanisms such as autophagy or mitochondrial fusion. Accordingly, these results provide a link between GRK2 levels and hepatic lipid homeostasis leading to NASH. [Conclusion]: Taken together, these results suggest a role for GRK2 in the establishment and/or development of NASH.