Letter to the editor: Cautious interpretation of the compensation of insulin‐mTORC1 activation to promote liver regeneration in the absence of hepatocyte β‐catenin

To the editor, We followed with interest the report by Shikai et al. on the underlying mechanisms driving liver regeneration (LR).1 This study concluded that the compensatory activation of the insulin‐mammalian target of rapamycin complex 1 (mTORC1) promoted LR in the absence of hepatocyte β‐catenin. We appreciated the authors' tremendous amount of work; however, some important issues required more explanation, especially because of the multiple internal pathways and complex mechanisms in LR. Mammalian target of rapamycin is a protein kinase that regulates cell growth, proliferation, and survival, as well as transcription and protein synthesis. A previous study has suggested the essential roles of mTORC1 in cell proliferation during LR in zebrafish.2 Raptor exists in mTORC1 as one of the specific binding partners. In this study, Raptor‐deficient mice did not provide a sufficient time window following partial hepatectomy (PH) to observe the process of LR, especially in double‐deletion mice that demised 12 h following PH. The function of Raptor might be too powerful to mask the regulatory role of β‐catenin in liver homeostasis and regeneration, and the compensatory or cooperative relationship between the mTORC1 and β‐catenin should be interpreted more cautiously. Second, Nadejda et al. identified mTORC1 as a major regulator of pancreatic α cell mass and glucagon secretion,3 which might explain the observed significant reduction in serum glucose in RaptorΔHC mice compared with control at 2 weeks after virus injection to some extent. Could the acute death of RaptorΔHC mice after PH be caused by hypoglycemia? It is necessary to monitor the level of post‐PH serum glucose, which might help improve the survival rate of gene‐edited mice. Third, in this study, the sequence of screening downstream products of β‐catenin and other pathways regulating LR was chaotic. It is suggested to improve the experimental flow chart, which might make the conclusion of the research more logical and persuasive, as there are many noncanonical signaling pathways in the liver that affect hepatocellular proliferation including Wnt/STOP and Wnt/TOR pathways.4 In addition, the sample size of some experiments was small or vague, which might threaten the reproducibility of this study. In conclusion, this study provided a potential therapeutic target for LR after acute liver injury or hepatectomy. However, a more logical research design is needed to improve translational value.