VEGF improves liver regeneration and survival after 90% hepatectomy in a rat model of fatty liver disease

Aims: Fatty liver disease is a clinical problem leading to enhanced morbidity and mortality after major liver resection. Previous studies suggested that Vascular Endothelial Growth Factor (VEGF) and Erythropoietin (EPO) may improve liver regeneration in a model of 90% hepatectomy (PH). We investigated the role of these mediators after PH in animals with diet-induced steatosis. Methods: Male Wistar rats were fed high-fat prior to 90% PH. Animals were treated either with EPO, VEGF or NaCl on postoperative day 0, 1 and 3 and sacrificed 24h or 7d after PH. Rats receiving 90% PH without HFD were used as control group. Survival rate (SV), liver regeneration and biochemical markers were assessed. Expression of inflammatory (TNF-a, IL-6) and apoptosis related (PUMA, Bcl-2) genes were measured by qRT-PCR. Results: High-fat diet induced steatosis after 11–12w (20%-60% hepatocytes affected) as confirmed by histopathology. 7d SV after PH was significantly decreased in HFD NaCl group compared to controls (50%vs.100%, p<0.05). Treatment with VEGF increased SV to 90%, whereas only 40% of the animals survived in the EPO group. Liver function were damaged after EPO treatment compared to the NaCl group (higher Bilirubin and PTT, p<0.05). Liver body weight ratio (LBWR), as regenerative index, was significantly lower in the NaCl group than in controls. VEGF improved LBWR significantly compared to NaCl or EPO treated animals (p<0.05). Inflammatory genes (TNF-a, IL-6) were up-regulated markedly in the EPO group 24h after PH. No significant changes of Bcl-2 and PUMA were detected. Conclusion: Steatosis severely impairs survival and regeneration after extensive liver resection. VEGF administration improved survival and stimulated liver regeneration, while EPO treatment was not beneficial. Perioperative VEGF treatment may be a novel option to improve the clinical outcome after major liver resection in patients with fatty liver disease.

fatty liver; hepatectomy; regeneration