CAMKK2‐dependent AMPK activation is required to drive cell cycle progression and hepatocyte proliferation after partial hepatectomy in the rat

Abstract

Liver regeneration is a unique repair response to tissue damage where normally quiescent liver cells reenter the cell cycle and undergo cell division, regaining the damaged or lost tissue, while maintaining the differentiated function of the tissue. In previous studies, we and others demonstrated that 70% partial hepatectomy (PHx) in the rat leads to an instantaneous (within 30 sec) release of up to 25% of ATP from the remnant liver. Released ATP served to activate purinergic receptors that enhance cellular stress responses and immediate‐early gene expression. ATP loss was mediated at least in part by a transient opening of connexin hemichannels and activation of stress signals and cell cycle progression was inhibited by hemichannel blocking peptides. The low ATP levels persist through the cell cycle progression and tissue ATP levels did not recover until 24–48 hrs post‐PHx. In the current study, we assessed the intracellular signaling events initiated by ATP loss. The decline in tissue ATP levels was accompanied by a persistent increase in ATP/AMP ratio and a transient activation of AMPK in the remnant liver, which peaked within 1 min after PHx, but then declined to basal levels within 15 min, despite the persistence of a low ATP/AMP. A second, extended phase of AMPK activation occurred, which peaked at 12–24 hrs after 70% PHx without being accompanied by major changes in tissue ATP/AMP ratios. This secondary AMPK activation in the regenerating rat liver accompanied cell cycle progression and DNA synthesis through G1‐S phase. After 30% PHx, a model that exhibits the hepatocyte priming events, but does not display the synchronized cell cycle progression and proliferation response, the initial ATP release and signaling events were comparable, but the secondary peak of AMPK activation is absent in the 30% PHx. Treatment with STO‐609, a selective inhibitor of CAMKK2, suppressed the second AMPK activation peak and inhibited hepatocyte proliferation after 70% PHx, suggesting the importance of calcium signaling in the regenerating liver. We conclude that an AMP‐independent CAMKK2‐mediated activation of AMPK is essential for effective cell cycle progression after PHx.Support or Funding InformationSupported by AA018873This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.