Large-Scale Profiling of Signaling Pathways Reveals a Distinct Demarcation between Normal and Extended Liver Resection

Borger, Pieter; Buzdin, Anton; Kachaylo, Ekaterina; Humar, Bostjan; Graf, Rolf; Clavien, Pierre-Alien

doi:10.3390/cells9051149

Cited by 3 publications

(2 citation statements)

References 22 publications

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“…Liver resection causes a rapid induction of HIF1α-associated main intracellular signaling pathways in a murine model of both standard (68%) and extended liver resection (86%) [52]. Activation of HIF-driven pathways could be a consequence of the immediate post-resection hypoxic conditions, caused by the overflow of oxygen-poor portal blood in a partially resected liver and the consequent buffering reduction in oxygen-rich arterial supply.…”

Section: Discussionmentioning

confidence: 99%

“…Interestingly, no later than 32 hours after standard two-third hepatectomy, hypoxiainduced pathways are rapidly downregulated. Hypoxia may thus be an important fine-tuning mechanism to induce liver regeneration [52], which acts in the very first days after liver resection. This might explain why even extreme resections performed in the setting of a reinforced hypoxia evolve favorably [4].…”

Section: Discussionmentioning

confidence: 99%

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Selective HIF stabilization alleviates hepatocellular steatosis and ballooning in a rodent model of 70% liver resection

et al. 2021

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Background: Small-for-size syndrome looms over patients needing liver resection or living-donor transplantation. Hypoxia has been shown to be crucial for the successful outcome of liver resection in the very early postoperative phase. While poorly acceptable as such in real-world clinical practice, hypoxia responses can still be simulated by pharmacologically raising levels of its transducers, the hypoxia-inducible factors (HIF). We aimed to assess the potential role of a selective inhibitor of HIF degradation in 70% hepatectomy (70%Hx). Methods: In a pilot study, we tested the required dose of roxadustat to stabilize liver HIF1α. We then performed 70%Hx in 8-week-old male Lewis rats and administered 25 mg/kg of roxadustat (RXD25) at the end of the procedure. Regeneration was assessed: ki67 and EdU immunofluorescent labeling, and histological parameters. We also assessed liver function via a blood panel and functional gadoxetate-enhanced magnetic resonance imaging, up to 47 hours after the procedure. Metabolic results were analyzed by means of RNA sequencing. Results: Roxadustat effectively increased early HIF1α transactivity. Liver function did not appear to be improved nor liver regeneration to be accelerated by the experimental compound. However, treated livers showed a mitigation in hepatocellular steatosis and ballooning, known markers of cellular stress after liver resection. RNA sequencing confirmed that roxadustat unexpectedly increases lipid breakdown and cellular respiration. Conclusions: Selective HIF stabilization did not result in an enhanced liver function after standard liver resection, but it induced interesting metabolic changes that are worth studying for their possible role in extended liver resections and fatty liver diseases.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Selective HIF stabilization alleviates hepatocellular steatosis and ballooning in a rodent model of 70% liver resection

et al. 2021

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Using proteomic and transcriptomic data to assess activation of intracellular molecular pathways

Buzdin

Tkachev

Zolotovskaia

et al. 2021

Advances in Protein Chemistry and Structural Biology

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Transcriptome sequencing and metabolome analysis reveal the metabolic reprogramming of partial hepatectomy and extended hepatectomy

Li,

Peng,

Chen

et al. 2023

BMC Genomics

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Surgical resection remains a critical treatment option for many patients with primary and secondary hepatic neoplasms. Extended hepatectomy (eHx) may be required for some patients with large tumors, which may cause liver failure and death. Partial hepatectomy (pHx) and eHx mouse models were constructed, liver tissues were sampled at 18, 36, and 72 h posthepatectomy. Transcriptome and metabolome analyses were employed to explore the different potential mechanisms in regeneration and injury between pHx and eHx. The results showed that eHx was associated with more severe liver injury and lower survival rates than pHx. Transcriptomics data showed there were 1842, 2129, and 1277 differentially expressed genes (DEGs) in eHx and 962, 1305, and 732 DEGs in pHx at 18, 36, and 72 h posthepatectomy, respectively, compared with the those in the sham groups. Compared with pHx, the number of DEGs in the eHx group reached a maximum of 230 at 18 h after surgery and decreased sequentially to 87 and 43 at 36 and 72 h. Metabolomics analysis identified a total of 1399 metabolites, and 48 significant differentially produced metabolites (DPMs) were screened between eHx and pHx. Combined analysis of DEGs and DPMs indicated that cholesterol metabolism and insulin resistance may be two important pathways for liver regeneration and mouse survival postextended hepatectomy. Our results showed the global influence of pHx and eHx on the transcriptome and metabolome in mouse liver, and revealed cholesterol metabolism and insulin resistance pathways might be involved in regeneration post-pHx and -eHx.

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Large-Scale Profiling of Signaling Pathways Reveals a Distinct Demarcation between Normal and Extended Liver Resection

Cited by 3 publications

References 22 publications

Selective HIF stabilization alleviates hepatocellular steatosis and ballooning in a rodent model of 70% liver resection

Selective HIF stabilization alleviates hepatocellular steatosis and ballooning in a rodent model of 70% liver resection

Using proteomic and transcriptomic data to assess activation of intracellular molecular pathways

Transcriptome sequencing and metabolome analysis reveal the metabolic reprogramming of partial hepatectomy and extended hepatectomy

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