Reduction and expansion of the glutamine synthetase expressing zone in livers from tetracycline controlled TGF-beta1 transgenic mice and multiple starved mice.
OBJECTIVE
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.
Ueberham
Elke
E
Institute of Biochemistry, Medical Faculty, University of Leipzig, Liebigstrasse 16, D-04103 Leipzig, Germany.
Arendt
Elisabeth
E
Starke
Michael
M
Bittner
Renate
R
Gebhardt
Rolf
R
D000818:Animals; D000900:Anti-Bacterial Agents; D017209:Apoptosis; D002455:Cell Division; D003598:Cytoskeletal Proteins / Q000378:metabolism; D015870:Gene Expression / Q000187:drug effects; D005974:Glutamate-Ammonia Ligase / Q000378:metabolism*; D008099:Liver / Q000201:enzymology* / Q000473:pathology; D008103:Liver Cirrhosis / Q000378:metabolism* / Q000473:pathology; D008115:Liver Regeneration; D051379:Mice; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA; D008822:Mice, Transgenic; D012333:RNA, Messenger / Q000032:analysis; D013217:Starvation / Q000378:metabolism*; D013752:Tetracycline; D015534:Trans-Activators / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000235:genetics*; D053773:Transforming Growth Factor beta1; D051176:beta Catenin
D000900:Anti-Bacterial Agents; C495267:CTNNB1 protein, mouse; D003598:Cytoskeletal Proteins; D012333:RNA, Messenger; C508961:Tgfb1 protein, mouse; D015534:Trans-Activators; D016212:Transforming Growth Factor beta; D053773:Transforming Growth Factor beta1; D051176:beta Catenin; D005974:Glutamate-Ammonia Ligase; D013752:Tetracycline