Triiodothyronine stimulates hepatocyte proliferation in two models of impaired liver regeneration.
OBJECTIVE
Liver regeneration is attenuated in old age and is substantially slower after 90% than after 70% partial hepatectomy (PH). We have previously demonstrated that the proliferative response to a primary mitogen is intact in aged mice, indicating that impaired liver regeneration is not due to loss of proliferative capacity. Here, we have investigated whether mitogenic effects of triiodothyronine (T3) could reverse the impaired regeneration of ageing or 90% hepatectomy, in the rat.


METHODS
T3 (20 microg/100 g body weight) was administered to 14-month-old rats subjected to 70% PH or to young rats subjected to 90% PH. Cell-proliferative capacity was determined by bromodeoxyuridine incorporation and microscopy and changes of cell cycle-related proteins were analysed by Western blot analysis.


RESULTS
Treatment of old intact rats with T3 increased cyclin D(1) expression that was followed by an enhanced proliferative response, the labelling index (LI), being 7.8% versus 1.3% of controls. T3 given before 70% PH stimulated regenerative response (LI was 10.8% versus 2.28%), and expression of cyclin D(1) and proliferating cell nuclear antigen (PCNA) 24 h after PH. Pre-treatment with T3 also improved the regenerative response of the liver after 90% hepatectomy (LI was 27.9% versus 14.2%).


CONCLUSIONS
These findings show in principle that mitogen-induced hyperplasia could be applied to human therapy in patients with reduced regenerative capacity or massive loss of hepatocytes.
Columbano
A
A
Department of Toxicology, Oncology and Molecular Pathology Unit, University of Cagliari, Italy. columbano@unica.it
Simbula
M
M
Pibiri
M
M
Perra
A
A
Deidda
M
M
Locker
J
J
Pisanu
A
A
Uccheddu
A
A
Ledda-Columbano
G M
GM
D000818:Animals; D015153:Blotting, Western; D018797:Cell Cycle Proteins / Q000378:metabolism; D002457:Cell Extracts; D002467:Cell Nucleus / Q000187:drug effects / Q000378:metabolism; D049109:Cell Proliferation / Q000187:drug effects; D019938:Cyclin D1 / Q000235:genetics / Q000378:metabolism; D050760:Cyclin-Dependent Kinase Inhibitor p27 / Q000378:metabolism; D005786:Gene Expression Regulation / Q000187:drug effects; D006498:Hepatectomy; D022781:Hepatocytes / Q000166:cytology* / Q000187:drug effects*; D008115:Liver Regeneration / Q000187:drug effects*; D008954:Models, Biological; D018809:Proliferating Cell Nuclear Antigen / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D014284:Triiodothyronine / Q000494:pharmacology*
D018797:Cell Cycle Proteins; D002457:Cell Extracts; D018809:Proliferating Cell Nuclear Antigen; D012333:RNA, Messenger; D014284:Triiodothyronine; D019938:Cyclin D1; D050760:Cyclin-Dependent Kinase Inhibitor p27