Role of AMP-activated protein kinase in the control of hepatocyte priming and proliferation during liver regeneration.

The enzyme AMP-activated protein kinase (AMPK) is the main energy sensor in cells and is responsible for controlling the balance of anabolic/catabolic processes under metabolic stress conditions. This metabolic control exerted by AMPK is critical for energy-demanding situations, such as liver regeneration. Immediately after partial hepatectomy (PH), the liver undergoes the priming phase, mediated by the proinflammatory cytokines tumor necrosis factor (TNF) and interleukin-6, which promote responsiveness of hepatocytes to growth factors, such as hepatocyte growth factor (HGF) and epidermal growth factor, which lead to proliferation. In addition to its metabolic function, AMPK is likely to be a key mediator in both hepatocyte priming and the proliferative phases, induced by TNF-α and HGF, respectively. TNF-α-induced AMPK activation has been shown to be necessary for nuclear factor κappa B (NF-κB)-induced inducible nitric oxide synthase expression and for blocking TNF-α-induced apoptosis. On the other hand, HGF-induced LKB1/AMPK activation has been found to play a critical role in controlling Hu antigen R cytosolic localization and endothelial nitric oxide synthase activation, and consequently Cyclin D1 and Cyclin A expressions, and nitric oxide generation, respectively. During PH, levels of S-adenosylmethionine (SAMe), the principal methyl donor in the liver, have to decrease to allow liver proliferation. Our studies also show that SAMe inhibits hepatocyte proliferation by controlling the hepatocyte's responsiveness to mitogenic signals such as HGF through the inhibition of AMPK activity. In summary, these data highlight the essential role of AMPK in controlling the balance between hepatocyte metabolic adaptations, cell cycle progression and apoptosis during liver regeneration.