The distinct regeneration pattern of small-for-size fatty liver graft – the significance of aldose reducatase signaling on oval cell activation

Abstract

BACKGROUND AND AIMS: Aldose Reductase (AR), which is involved in “polyol pathway”, has been found to be up-regulated in prolonged cardiac ischemia. We have identified AR to be specifically over-expressed in small-for-size fatty liver graft by cDNA microarray screening after liver transplantation. We aim to investigate the mechanism of AR on small-for-size fatty liver graft regeneration. MATERIALS AND METHODS: Rat orthotopic liver transplantation model using recipients with cirrhotic liver was established. Small-for-size fatty (40% fatty change) or normal grafts were applied. Graft regeneration patterns were compared by Ki67 (hepatocyte) and OV-6 (stem like cell) staining. Intragraft gene expression of AR was detected by RT-PCR. The gene signaling linking to energy metabolism and liver regeneration was analyzed. The role of AR on liver regeneration and glucose metabolism were further studied in AR-/- mice with fatty liver that underwent major hepatectomy. RESULTS: Normal hepatocytes regeneration (with Ki67 staining) was delayed, but a number of activated oval cells (OV-6 staining) were found in small-for-size fatty grafts during the first 2 weeks after liver transplantation. Intragraft gene expression of AR was significantly increased in small-for-size fatty graft compared to normal graft at day 2 after transplantation (4.31 vs 2.13 folds of normal liver, p=0.005). The up-regulated AR expression correlated with down-regulation of cell signaling of liver regeneration (PCNA etc) and metabolism (FABP and PPAR etc). In the in vivo functional study, hepatocytes regeneration pathway (Ki67 and BrdU staining) was promoted and oval cell activation was inhibited in AR-/- mice compared to wild type mice with fatty liver after major hepatectomy. Blood glucose was also restored in fatty AR- /-mice compared to wild type mice (6.1mmol/L vs 3.45 mmol/L p=0.01) at day 2 after major hepatectomy. CONCLUSION: Activation of oval cells instead of normal hepatocytes regeneration was present in small-for-size fatty liver graft. Over-expression of Aldose Reductase (AR) initiated oval cell activation and inhibited hepatocyte regeneration by impairment of energy metabolism through FABP/PPAR pathway in small-for-size fatty liver graft.