Abstract
Background: the role of bile acid (BA)-induced farnesoid X receptor (Fxr) signaling in liver regeneration following associating liver partition and portal vein ligation for staged hepatectomy (ALPPS) was investigated in a rat model. Methods: Male Wistar rats underwent portal vein ligation (PVL) (n = 30) or ALPPS (n = 30). Animals were sacrificed pre-operatively and at 24, 48, 72, or 168 h after intervention. Regeneration rate, Ki67 index, hemodynamic changes in the hepatic circulation, and BA levels were assessed. Transcriptome analysis of molecular regulators involved in the Fxr signaling pathway, BA transport, and BA production was performed. Results: ALLPS induced more extensive liver regeneration (p < 0.001) and elevation of systemic and portal BA levels (p < 0.05) than PVL. The mRNA levels of proteins participating in hepatic Fxr signaling were comparable between the intervention groups. More profound activation of the intestinal Fxr pathway was observed 24 h after ALPPS compared to PVL. Conclusion: Our study elaborates on a possible linkage between BA-induced Fxr signaling and accelerated liver regeneration induced by ALPPS in rats. ALPPS could trigger liver regeneration via intestinal Fxr signaling cascades instead of hepatic Fxr signaling, thereby deviating from the mechanism of BA-mediated regeneration following one-stage hepatectomy.
Highlights
Liver regeneration is fundamental to successful and safe liver resections
Accelerated Liver Growth and Cell Proliferation following ALPPS. Both portal vein ligation (PVL) and ALPPS induced growth of the right part of the median lobe from 24 h to 168 h (Figure 3A), whereby an increase in liver mass of the non-ligated lobes was higher in the ALPPS group compared to the PVL group at all time points
Cell proliferation in the nonligated lobes in both groups was higher from 24 h to 72 h versus baseline and abated towards baseline levels at the end of the experiment (Figure 3B,C)
Summary
Liver regeneration is fundamental to successful and safe liver resections. Approximately 45% of patients with advanced tumors undergo extensive partial hepatectomy (PHx) with curative intent [1]. Portal vein occlusion techniques such as portal vein embolization (PVE) and portal vein ligation (PVL) are standardly employed before PHx to pre-operatively increase FLR size [3]. The function of BAs in liver regeneration and the involvement of hepatic and intestinal Fxr signaling in this process were investigated in rats subjected to ALPPS and juxtaposed to PVL. It was hypothesized that ALPPS would cause an increase in the plasma levels of BAs that would activate the Fxr-Foxm1b signaling axis in the hepatocytes comprising the FLR, translating to liver growth. The present study focused on several key aspects of this hypothesis
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