TY - JOUR
T1 - SHP2 inhibition enhances Yes-associated protein-mediated liver regeneration in murine partial hepatectomy models
AU - Watkins, Ryan D.
AU - Buckarma, Eee LN H.
AU - Tomlinson, Jennifer L.
AU - Mccabe, Chantal E.
AU - Yonkus, Jennifer A.
AU - Werneburg, Nathan W.
AU - Bayer, Rachel L.
AU - Starlinger, Patrick P.
AU - Robertson, Keith D.
AU - Wang, Chen
AU - Gores, Gregory J.
AU - Smoot, Rory L.
N1 - Publisher Copyright:
© 2022, Watkins et al. This is an open access article published under the terms of the Creative Commons Attribution 4.0 International License.
PY - 2022/8/8
Y1 - 2022/8/8
N2 - Disrupted liver regeneration following hepatectomy represents an "undruggable"clinical challenge associated with poor patient outcomes. Yes-associated protein (YAP), a transcriptional coactivator that is repressed by the Hippo pathway, is instrumental in liver regeneration. We have previously described an alternative, Hippo-independent mechanism of YAP activation mediated by downregulation of protein tyrosine phosphatase nonreceptor type 11 (PTPN11, also known as SHP2) inhibition. Herein, we examined the effects of YAP activation with a selective SHP1/SHP2 inhibitor, NSC-87877, on liver regeneration in murine partial hepatectomy models. In our studies, NSC-87877 led to accelerated hepatocyte proliferation, improved liver regeneration, and decreased markers of injury following partial hepatectomy. The effects of NSC-87877 were lost in mice with hepatocyte-specific Yap/Taz deletion, and this demonstrated dependence on these molecules for the enhanced regenerative response. Furthermore, administration of NSC-87877 to murine models of nonalcoholic steatohepatitis was associated with improved survival and decreased markers of injury after hepatectomy. Evaluation of transcriptomic changes in the context of NSC-87877 administration revealed reduction in fibrotic signaling and augmentation of cell cycle signaling. Cytoprotective changes included downregulation of Nr4a1, an apoptosis inducer. Collectively, the data suggest that SHP2 inhibition induces a pro-proliferative and cytoprotective enhancement of liver regeneration dependent on YAP.
AB - Disrupted liver regeneration following hepatectomy represents an "undruggable"clinical challenge associated with poor patient outcomes. Yes-associated protein (YAP), a transcriptional coactivator that is repressed by the Hippo pathway, is instrumental in liver regeneration. We have previously described an alternative, Hippo-independent mechanism of YAP activation mediated by downregulation of protein tyrosine phosphatase nonreceptor type 11 (PTPN11, also known as SHP2) inhibition. Herein, we examined the effects of YAP activation with a selective SHP1/SHP2 inhibitor, NSC-87877, on liver regeneration in murine partial hepatectomy models. In our studies, NSC-87877 led to accelerated hepatocyte proliferation, improved liver regeneration, and decreased markers of injury following partial hepatectomy. The effects of NSC-87877 were lost in mice with hepatocyte-specific Yap/Taz deletion, and this demonstrated dependence on these molecules for the enhanced regenerative response. Furthermore, administration of NSC-87877 to murine models of nonalcoholic steatohepatitis was associated with improved survival and decreased markers of injury after hepatectomy. Evaluation of transcriptomic changes in the context of NSC-87877 administration revealed reduction in fibrotic signaling and augmentation of cell cycle signaling. Cytoprotective changes included downregulation of Nr4a1, an apoptosis inducer. Collectively, the data suggest that SHP2 inhibition induces a pro-proliferative and cytoprotective enhancement of liver regeneration dependent on YAP.
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U2 - 10.1172/jci.insight.159930
DO - 10.1172/jci.insight.159930
M3 - Article
C2 - 35763355
AN - SCOPUS:85135599246
SN - 2379-3708
VL - 7
JO - JCI Insight
JF - JCI Insight
IS - 15
M1 - e159930
ER -