Reduction and expansion of the glutamine synthetase expressing zone in livers from tetracycline controlled TGF-beta1 transgenic mice and multiple starved mice.

BACKGROUND/AIMS: To learn more about tissue remodelling in fibrotic livers of tetracycline-controlled TGF-beta1 transgenic mice (TGF-beta1-on-mice) and during regeneration after removal of the fibrotic stimulus (off-mice), we investigated the expression of glutamine synthetase (GS), an exclusive pericentrally expressed enzyme.

METHODS

GS was localised immunohistochemically and quantified by real-time RT-PCR and enzymatic activity measurement. Apoptosis in livers of TGF-beta1-on-mice was demonstrated by in situ apoptosis detection kit (TUNEL reaction).

RESULTS

Livers of TGF-beta1-on-mice harbour a reduced number of GS-positive hepatocytes and expression of GS is downregulated, while multiple starved mice serving as controls for malnutrition during TGF-beta1 exposure surprisingly showed an impressive amplification of GS-positive hepatocytes. Apoptotic events were frequent around central veins in livers of TGF-beta1-on-mice, while in multiple induced mice apoptosis was dominant around all vessels and weak in midzonal areas. During regeneration from fibrosis, control levels were regained within 21 days. Beta-catenin was dislocated from plasma membrane to cytoplasm exclusively in pericentral hepatocytes during a short time slot after a unique expression of TGF-beta1.

CONCLUSIONS

Reduction of GS in TGF-beta1-on-mice results from apoptosis of GS-positive hepatocytes rather than downregulation of GS expression. Beta-catenin seems involved in the recovery of GS-positive hepatocytes.