341 Liver Regeneration and Survival After Subtotal Hepatectomy in a Fatty Liver Model is Improved by VEGF

Abstract

Background and Aims: Westernized dietary habits around the world lead to higher incidence of fatty liver disease, which enhance morbidity and mortality after major liver resection. Previous works in our group suggested that liver regeneration in a model of subtotal (90%) hepatectomy (PH) using normal rats may be improved by Vascular Endothelial Growth Factor (VEGF) and Erythropoietin (EPO). Thus, we investigated the role of these mediators after PH in animals with diet-induced steatosis. Methods: Male Wistar rats were fed with a high-fat diet (HFD) for 11-12 weeks and then subjected to 90% PH. On postoperative day 0, 1 and 3 animals were treated either with EPO, VEGF or NaCl and sacrificed at 24h or 7 days after hepatectomy. Rats receiving 90% PH without HFD were used as control group. The survival rate (SV), liver regeneration and biochemical markers were assessed. Expression of inflammatory (TNF-α, IL-6) and apoptosis related (PUMA, Bcl-2) genes were measured by quantitative RT-PCR. Results: After 11-12 weeks high-fat diet led to steatosis (20%60% hepatocytes affected) as confirmed by histopathology. HFD NaCl animals exhibited a significantly impaired SV in comparison to the control group (50% vs. 100%, p<0.05) within 7 days. VEGF treatment improved the survival rate to 90%, whereas only 40% of the animals survived in the EPO group. Significantly elevated serum bilirubin and PTT values (p<0.05) were detected after EPO treatment compared to the NaCl group. Liver body weight ratio (LBWR), as indicator for regeneration, was significantly lower in the NaCl group than in the control group. VEGF improved LBWR significantly in comparison to animals treated with NaCl or EPO (P < 0.05). In contrast, the pro-regenerative genes TNF-α and IL-6 were markedly up-regulated in the EPO group at 24 hours after surgery. Bcl-2 and PUMA exhibited no significant changes in all groups. Conclusion: Survival and regeneration after extensive liver resection is severely impaired by steatosis.While VEGF administration improved survival and enhanced liver regeneration, EPO treatment was not beneficial. Short-term perioperative VEGF-treatment as possible new therapeutic option could improve the clinical outcome after major liver resection in patients with fatty liver disease.