Increased hepatic glucosylceramide levels in GBA2 deficient mice are beneficial during the early phase of liver regeneration

Introduction: Gba2 knockout mice accumulate the glycolipid glucosylceramide in different tissues, including the liver. Glycolipids are a class of cellular membrane lipids that differ from the regular membrane phospholipids in a remarkable variation in its head group structures. This suggests that glycolipids serve specialized functions in cell signaling, differentiation and recognition processes (van Meer et al. 2003). Different studies have suggested a special role of glycolipids in cell cycle and cell proliferation. Our aim was to investigate the role of glucosylceramide in liver regeneration using the two-thirds partial hepatectomy model according to the method of Higgins and Anderson.

Methods: Groups of five 10–12 week old Gba2 knockout and wild-type animals were anesthetized and subjected to 70% partial hepatectomy. At 0, 6h, 12h, 24h, 48h, 3d, 5d and 7d post-hepatectomy mice were killed and the remnant livers were snap frozen or fixed in 4% paraformaldehyde. Cell proliferation was determined by bromodeoxyuridine (BrDU) incorporation, and cell cycle-related proteins were analyzed by immunoblots.

Results and conclusions: The proliferation rate and the expression of cell cycle-related proteins, such as cyclin D, are markedly increased in GBA2 deficient mice until the second day post-hepatectomy. This difference between GBA2 deficient mice and control animals disappears after the third day of liver regeneration. At the same time, the liver regeneration index (liver to body weight ratio) starts significantly to decrease in GBA2 deficient mice as compared to the wild-type animals. In conclusion, our data suggests that the accumulation of glucosylceramide may be beneficial in the early phase of liver regeneration. Later on, other factors appear to outweigh the potential advantage of glucosylceramide, which are absent in the Gba2 knockout mice.

glucosylceramide - liver regeneration