In the situation of obesity, fatty liver and aging, organs and cells are thought to be potentially under stresses. In this respect, we have been reporting that liver shows impaired response to external stresses
(J Gastroenterol Hepatol 2007, Laboratory Invest 2010, etc.). In fatty liver, the suppression of intranuclear kinase, Wee1/Myt1, was found out, which inhibited the phosphorylation of Cdc2 resulting in retarding cell proliferation. Moreover, fatty liver also showed increased response to oxidative damage in response to external stimuli. We demonstrated that the increase of intracellular oxidative stressed by aging-related factor, p66Shc, and the decrease of anti-apoptotic activity lowered stress responses of liver in aged condition.
We have also investigated that the signaling molecules regarding cell proliferation and survival regulated the metabolism of fatty acid and sugar in the liver. Particularly, Jak/STAT3 pathway controls hepatocyte lipid synthesis through SREBP-1/FAS (Fatty Acid Synthase), and it also affects sugar metabolism by regulating G-6-PC/PEPCK through PGC-1.
This evidence showing direct influence of cellular signaling molecules on those metabolism are epoch-making, and it suggests that the stress response of local organ reflects the changes of metabolic activity, resulting in impinging on whole bodies.（Nat Med 2004）