Impaired liver regeneration after subtotal 90% hepatectomy is associated with suppression of NF-B activation and proregenerative genes

Introduction: A main concern regarding extended hepatectomies (i.e. in tumor resections or in living donor liver transplantation [LDLT]) is that the small remnant liver may lead to liver failure or death of patient or donor. Therefore, we investigated the molecular events after subtotal hepatectomy in a rat model. Methods: Male Wistar rats were subjected to a 70% or 90% partial liver resection. The regenerating liver was explanted at different time points after operation. Sham operated animals served as controls. Clinical and laboratory parameters (liver-body-weight ratio and liver function tests) were assessed postoperatively. Total RNA was isolated from the liver tissue to investigate expression of factors relevant for liver regeneration (HGF, TNF-α, IL–6, IRAKM, TGF-α/β) by quantitative real time PCR. Nuclear proteins (NF-κB, STAT3) were extracted from liver tissue to determine activation of transcription factors important for liver regeneration. Apoptosis after resection was analysed by TUNEL-staining of tissue sections. Results: After 70% resection, NF-κB activation was detectable until 12h p.o., while no activation could be found after 90% resection. We found a strong activation of STAT3 2h p.o. in both groups. Quantitative real time PCR showed a suppression of TNF-α after 90% resection, compared to a strong upregulation after 70% resection at 24h p.o. Surprisingly, we detected downregulation of TGF-α and TGF-β 24h and 48h after 70% hepatectomy, while both genes were unchanged after 90% resection. HGF showed no significant differences between the different groups. TUNEL-staining of tissue sections revealed elevated apoptosis rates in the 70% resection group until 24h p.o. In the animals which underwent 90% resection we found a strong increase of the TUNEL-index only directly after surgery and 7d p.o. Conclusion: Subtotal hepatectomy leads to a suppressed and delayed regeneration of the remnant liver, which is accompanied by delayed activation of NF-κB, which again is associated with a suppression of regenerative genes. TUNEL data and expression of anti-regenerative genes suggest that remodelling processes in the liver occur earlier during regeneration after 70% resection than in subtotal hepatectomy. Strategies aiming towards an increased activation of NF-κB at an early time point after subtotal hepatectomy could possibly improve the clinical outcome of extended hepatectomies.

90% hepatectomy - NF-κB - liver regeneration - proregenerative genes