Recovery from liver damage requires regeneration. Ethanol (EtOH) delays induction of hepatocyte DNA synthesis by partial hepatectomy (PH). Thus, it may promote chronic liver disease by inhibiting liver regeneration. We have been trying to characterize the mechanisms involved by first defining how liver injury normally triggers hepatocyte replication and then, identifying which of these mechanisms is altered by EtOH. Progress in both areas suggests this GENERAL HYPOTHESIS: EtOH disturbs normal liver regeneration because it causes mature hepatocytes to accumulate excessive reactive oxygen species (ROS). The ROS inhibit mature hepatocyte replication and cause senescence. This, in turn, promotes the proliferation of less differentiated liver cells, delaying recovery.
Aim #1 is to delineate mechanisms for EtOH-related mitoinhibition in mature hepatocytes. Our data support the hypothesis that EtOH inhibits proliferation and induces replicative senescence in hepatocytes by exacerbating mitochondrial ROS production. We will evaluate this paradigm: Chronic EtOH ? mitochondrial GSH depletion ?changes in ROS regulatory enzyme activities? increased H2O2?p38 MAPK activation? inhibited cyclin D-1 transcription? reduced Cyclin D-1 protein? failure to sequester phospho-Stat3 in the cytosol? increased nuclear accumulation of Stat3? increased transcription of p21? inhibited cyclin D-1/cdk activity? G-1/S arrest.
Aim #2 is to define the consequences of EtOH-related senescence for mature hepatocytes. Our data demonstrate that PH increases ROS production and DNA damage, inducing the DNA repair enzyme, poly(ADP-ribose)polymerase (PARP). PARP activation transiently reduces hepatic ATP stores. EtOH ingestion chronically increases ROS-related DNA damage, necessitating chronic PARP activity, which may deplete ATP stores to levels that prevent hepatocyte replication and limit further activation of PARP. Our hypothesis is that senescent hepatocytes have DNA damage due to chronic, EtOH-related increases in ROS. We will evaluate this concept: Chronic EtOH? increased H2O2 before PH? baseline DNA damage? increased PARP activity before PH? reduced ATP? delayed cell cycle progression and insufficient induction of PARP after PH? accumulation of senescent hepatocytes with DNA damage.
Aim #3 is to determine if (and how) EtOH-related mitoinhibition of mature hepatocytes triggers the expansion of less differentiated liver cell populations. We have evidence that immature liver """"""""oval"""""""" cells accumulate in the liver during EtOH exposure and find that injury-related factors modulate the oval cell accumulation in mice with hepatic oxidative stress. Our hypothesis is that some of the same factors that inhibit proliferation and cause senescence in mature hepatocytes increase hepatic oval cells during chronic EtOH exposure. We will evaluate this model: Chronic EtOH? hepatic oxidative stress? increased induction of TNFa and other cytokines plus altered activity of autonomic nervous system-->increased progenitor ceil proliferation and/or decreased differentiation and cell death? hepatic accumulation of oval cells. Because EtOH inhibits the replication of mature hepatocytes, regeneration after alcoholic liver injury requires hepatocyte progenitors. Defining mechanisms that regulate these cells is key to improving recovery ? ?
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