Liver regeneration is suppressed in small-for-size liver grafts after transplantation: involvement of c-Jun N-terminal kinase, cyclin D1, and defective energy supply.
BACKGROUND
Small-for-size liver grafts have decreased survival compared to full-size grafts. This study investigated mechanisms of suppression of liver regeneration in small-for-size grafts.


METHODS
Rat liver explants were reduced in size to 50% and implanted into recipients of different body weights, resulting in graft weight/standard liver weights of approximately 50% (half-size) and approximately 25% (quarter-size).


RESULTS
Hepatic cellular 5-bromo-2'-deoxyuridine (BrdU) incorporation increased from 0.2% after sham operation to 2%, 18%, and 1.2% in full-size, half-size, and quarter-size grafts, respectively. Graft weight did not increase in full- and quarter-size grafts but increased 40% in half-size grafts. By contrast, apoptosis remained low (< or =0.7%) and stem cells did not increase in all conditions. Phospho-c-Jun increased 27-fold in half-size grafts but only sevenfold in quarter-size grafts. Activating protein-1 activation increased 14-fold in half-size grafts but only fivefold in quarter-size grafts. Cyclin D1 (CyD1), which was barely detectable in full- and quarter-size grafts, increased 8.3-fold in half-size grafts. Adenosine 5'-triphosphate (ATP) per gram tissue decreased 70% in quarter-size grafts. Treatment of quarter-size grafts with radical scavenging C. sinenesis polyphenols (20 microg/ml) increased BrdU labeling and weight gain to 35% and 56%, respectively, reversed inhibition of CyD1 expression, c-Jun phosphorylation, and AP-1 activation in quarter-size grafts compared to half-size grafts, and restored ATP levels to 75%.


CONCLUSIONS
Liver regeneration is stimulated in half-size grafts but suppressed in quarter-size grafts. Defective liver regeneration in small grafts is associated with an inhibition of the c-Jun N-terminal kinase/c-Jun and CyD1 pathways and compromised energy production.
Zhong
Zhi
Z
Department of Cell and Developmental Biology, University of North Carolina, Chapel Hill, 29425, USA.
Schwabe
Robert F
RF
Kai
Yoichiro
Y
He
Lihua
L
Yang
Liu
L
Bunzendahl
Hartwig
H
Brenner
David A
DA
Lemasters
John J
JJ
D000818:Animals; D019938:Cyclin D1 / Q000378:metabolism*; D004195:Disease Models, Animal; D004734:Energy Metabolism; D005419:Flavonoids / Q000494:pharmacology; D017228:Hepatocyte Growth Factor / Q000032:analysis; D015850:Interleukin-6 / Q000032:analysis; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism*; D008115:Liver Regeneration / Q000187:drug effects / Q000502:physiology*; D016031:Liver Transplantation / Q000276:immunology / Q000502:physiology*; D008297:Male; D010636:Phenols / Q000494:pharmacology; D059808:Polyphenols; D011168:Portal System; D051381:Rats; D011917:Rats, Inbred Lew; D013234:Stem Cells / Q000166:cytology; D014409:Tumor Necrosis Factor-alpha / Q000032:analysis
D005419:Flavonoids; D015850:Interleukin-6; D010636:Phenols; D059808:Polyphenols; D014409:Tumor Necrosis Factor-alpha; D019938:Cyclin D1; D017228:Hepatocyte Growth Factor; D048031:JNK Mitogen-Activated Protein Kinases