Upregulation of ureagenesis may be pivotal for survival of post-hepatectomy liver failure in rats

Abstract

Background: Post-hepatectomy liver failure (PHLF) is a feared complication with high mortality that may occur after extended partial hepatectomy (PH). Due to the risk of PHLF, size of PH and hence the size of the future liver remnant (FLR) may limit curability if malignancy is widespread in the liver. With the aim to identify proteins specific to the regenerative process of minimal-size FLR (MSFLR) and during PHLF, we characterized protein expressions on different PODs by sizes of PH. Material & Methods: A total of 104 male Wistar rats subjected to 30%, 70%, or 90% PH (MSFLR in rats); sham or no operation. Blood and liver tissue harvested at POD1, 3, and 5 (n=8 per group). Protein expression was assessed by unsupervised proteomic profiling by 2D-PAGE and liquid-chromatography mass-spectrometry. In addition, plasma-ammonia levels were measured at time of euthanization. Results: In all,1,035 protein spots were identified of which 54 were significantly differentially expressed between groups (FDR<0.05, fold change>2) and identifiable. Strikingly, during PHLF, represented by the PH(90%) POD1-group, specifically protein expressions favoring urea cycle activity were changed by upregulation of Carbamoyl phosphate synthase-1 (CPS-1), Ornithine transcarbamylase (OTC) and Arginase-1 (ARG-1) with coexisting downregulation of Ornithine aminotransferase (OAT) and Propionyl-CoA carboxylase alpha chain (PCCA)(Fig. 1). Plasma-ammonia was highly elevated at POD1 after PH(90%) followed by a prompt decrease (Fig. 1). Conclusions: The protein expression of the MSFLR of surviving rats during PHLF is changed in favor of urea cycle enhancement. Our Results indicate that ammonia elimination by enhanced urea-cycle capacity in hepatocytes plays a key role in survival after extensive PHs and potential PHLF.