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.