Protective effect of peroxisome proliferator-activated receptor-α in regulating the early inflammation response to extended hepatectomy from a comparative transcriptomic analysis

Background: The regulation mechanism of post-operative hepatic failure and small-for-size syndrome remains unclear. Thus, we aimed to analyze the molecular profiles following extended hepatectomy and identify the therapeutic target. Methods Major hepatectomy and extended hepatectomy were performed in the rat model, and the remnant livers were obtained dynamically for the high-throughput transcriptome analysis to identify the differentially expressed genes (DEGs). The general framework for weighted gene co-expression network analysis (WGCNA) was employed to explore the expression patterns of DEGs. The expression and function of the selected DEG from the WGCNA was further verified following hepatectomy in the human and rat. Results DEGs after major hepatectomy and extended hepatectomy were detected by transcriptomics. WGCNA identified 10 distinct gene co-expression modules according to the correlation between module eigengene and different postoperative time-points. The magenta module (gene count: 289) and the lightcyan module (gene count: 484) were found positively correlated with major hepatectomy instead of extended hepatectomy. In the lightcyan module, peroxisome proliferator-activated receptor-α (PPARα) was selected and found the down-regulation in the remnant liver following extended (marginal) hepatectomy in rats and humans. Besides, administration of PPARα agonist attenuated hepatic inflammation injury while PPARα antagonist increased liver inflammation injury after extended hepatectomy in rats, marked by the significantly changed aminotransferases, tumor necrosis factor-α and interleukin - 6 levels in the plasm, and histological Suzuki criteria. Conclusion DEGs and their molecular profiles after extended hepatectomy were identified, and PPARα could be a potential therapy target for small-for-size syndrome.