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 50% (half-size) and 25% (quarter-size). Results.Hepaticcellular5-bromo-2-deoxyuridine(BrdU)incorporationincreasedfrom0.2%aftershamoperationto 2%,18%,and1.2%infull-size,half-size,andquarter-sizegrafts,respectively.Graftweightdidnotincreaseinfull-and quarter-size grafts but increased 40% in half-size grafts. By contrast, apoptosis remained low (0.7%) and stem cells didnotincreaseinallconditions.Phospho-c-Junincreased27-foldinhalf-sizegraftsbutonlysevenfoldinquarter-size grafts.Activatingprotein-1activationincreased14-foldinhalf-sizegraftsbutonlyfivefoldinquarter-sizegrafts.Cyclin D1(CyD1),whichwasbarelydetectableinfull-andquarter-sizegrafts,increased8.3-foldinhalf-sizegrafts.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 g/ml) increased BrdU labeling and weight gain to 35% and 56%, respectively,reversedinhibitionofCyD1expression,c-Junphosphorylation,andAP-1activationinquarter-sizegrafts 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.