Molecular mechanisms of liver regeneration and protection for treatment of liver dysfunction and diseases

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Liver regeneration is a necessary process which most liver damage depends on for its recovery. It is achieved by a complex interaction network consisting of liver cells (hepatocytes, Kupffer cells, sinusoidal endothelial cells, hepatic stellate cells and stem cells) and extra-hepatic organs (thyroid gland, adrenal gland, pancreas, duodenum and autonomous nervous system). The restoration of liver volume depends on the hepatocyte proliferation which includes initiation/proliferation/termination phases. Hepatocytes are 'primed' mainly by Kupffer cells via cytokines (IL-6 and TNF-alpha) and then 'proliferation' and 'cell growth' of hepatocyte are induced by the stimulations of cytokines and growth factors (HGF and TGF-alpha). Liver regeneration is achieved by cell proliferation and cell growth, where IL-6/STAT3 pathway and PI3-K/PDK1/Akt pathway play pivotal roles, respectively. IL-6/STAT3 pathway regulates hepatocyte proliferation via cyclin D1/p21 and protects against cell death by up-regulating FLIP, Bcl-2, Bcl-xL, Ref1 and MnSOD. PI3-K/PDK1/Akt is known to be responsible for regulation of cell size via its downstream molecules such as mTOR in addition to its survival, anti-apoptotic and anti-oxidative properties. Although the molecular mechanisms of liver regeneration have been actively studied, it is required to elucidate and leverage the mechanisms of liver regeneration for the sufficient treatment of liver diseases.

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