Reply.

Abstract

We thank the authors of Hu et al. for their comments on our study.1 We understand the complexity of signaling pathways that can make the current study complicated for some to understand but are confident of its relevance and reproducibility. With regards to concern 1, relationship between hepatic mechanistic target of rapamycin complex 1 (mTORC1) and β‐catenin was shown in four ways. First, we identified compensatory activation of mTORC1 and its downstream effectors in β‐cateninΔHC mice after hepatectomy. Second, we showed demise of RaptorΔHC‐β‐cateninΔHC mice by 12 h and of RaptorΔHC mice by 48 h posthepatectomy. Third, RaptorΔHC mice without any challenge died at 40 days and showed early proliferative β‐catenin activation. RaptorΔHC‐β‐cateninΔHC mice showed demise by 30 days. Lastly, pharmacological inhibition of mechanistic target of rapamycin led to impaired liver regeneration (LR) and demise of β‐cateninΔHC by 14 days postsurgery. Collectively, our data demonstrate compensatory interplay between mTORC1 and β‐catenin signaling. For point 2, AAV8‐TBG–mediated gene deletion in our model should not disrupt pancreatic mTORC1 signaling.2 Decreased serum glucose level in Raptor knockouts has been reported due to compensatory AKT activation.3 Deleting Akt2 in the Raptor knockouts reversed changes in serum glucose and may be mediated by AKT‐driven glycogen synthase kinase 3 beta (GSK3β) phosphorylation and inactivation.3 We also observed increased AKT activation and GSK3β inactivation in RaptorΔHC mice. Thorough understanding of the intricacies of LR is important to appreciate the sequence of experimentation in our study. Also, because of the numbers of mice and time points, it is impossible to show every piece of data, but appropriate statistics were always included. Analysis of known mitogenic and developmental pathways during LR in β‐cateninΔHC mice was inconsequential. We identified insulin‐mTORC1 signaling as one possible mechanism driving LR in these mice. We did not address the role of Wnt‐dependent stabilization of proteins signaling, which may be agnostically contributing to cell division in LR.4 It is unlikely that Wnt/mTORC1 pathway signaling is playing a role in LR in β‐cateninΔHC mice because we did not see any difference in LDL related protein 6 phosphorylation.5 Eventually, we agree that, as a responsible researcher, it is pertinent to be cautious in interpreting every scientific study because there often are multiple explanations underlying an observation.