Beta-glucosidase 2 knockout mice with increased glucosylceramide show impaired liver regeneration

Background and aims Glycolipids have been shown to serve specialized functions in cell signalling, proliferation and differentiation processes, which are all important during liver regeneration. We previously generated beta-glucosidase 2 (GBA2) knockout mice that accumulate the glycolipid glucosylceramide in various tissues, including the liver. The present study addressed the role of GBA2-deficiency and subsequent glucosylceramide accumulation in liver regeneration. Methods Gba2 knockout and wild-type mice were subjected to two-third partial hepatectomy. Mice were sacrificed at different time points, blood was collected, and the remnant liver was removed. Glucosylceramide and ceramide were quantified using mass spectrometry from whole liver and isolated hepatocytes. Serum and hepatocytic supernatant of IL-6, TNF-a and TGF-beta levels were measured using ELISA. Cell signalling proteins were analysed using immunoblots. Results Regenerating liver after partial hepatectomy showed a significant increase of hepatic glucosylceramide in GBA2-deficient mice compared to controls. Accumulation of glucosylceramide was associated with a delay in liver regeneration and reduced serum levels of IL-6 and TNF-a. Furthermore, reduced IL-6 led to decreased expression of the phosphorylated form of the signal transducer and activator of transcription 3 (P-STAT3). Conclusions We conclude that increased glucosylceramide affects cytokine- and growth factor-mediated signalling pathways during liver regeneration. Thus, the repression of IL-6/STAT3 signalling pathway seems to be one of the mechanisms for the delay of liver regeneration in GBA2-deficient mice.