Ethanol Effects on the Transcriptional Regulatory Network in Liver Regeneration

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PROJECT SUMMARY Liver regeneration is a program with a broad range of applications that is designed to maintain a healthy state of the tissue. When the liver gets exposed to severe damage, there is an active repair response that can use the functional cells and help them expand to the optimal size for that tissue. Many toxins and related treatments are capable of damaging the liver tissue to the point where only a modest quantity of liver function remains. However, under these conditions the liver is uniquely positioned to repair its structure and recover the original tissue mass and it is these processes that help maintain liver function, referred to as Liver Regeneration. The repair process has multiple productive applications. However, it may be derailed by processes such as the heavy consumption of alcoholic beverages and as a result, it is subject to monitoring that may derail its usefulness. Unusually, we recently discovered that exposure of our rats to ethanol in their food will chronically lead to a health crisis upon liver injury only in male rats, whereas female rats did not suffer from this affliction. This finding matched our prior studies that had demonstrated that females are more resistant to some types of alcohol-related injury. Moreover, we have developed a research program in which males are subject to a variety of alcohol-related injuries that females are protected from. These findings are correlated with the individual tests for sensitivity of the liver regeneration process resolved in specific interactions. The Specific Aims are summarized here to enable the recovery of the critical points to identify where the problems are located. These aims include (a) studies to test the hypothesis that ethanol affects the tissue state balance of metabolic compensatory adjustments and proliferation to disrupt the integrate response to PHx, (b) studies to test the hypothesis that interlinked cell state transitions across multiple cell types govern the integrative response to ethanol-mediated disruption in a sex- dependent manner; and (c) studies to identify the renormalization of the ethanol-blocked deficiencies in hepatocyte proliferation by normalizing early phase transcriptional regulatory events; We will bridge between animal models and human ALD in these Aims by evaluating the animal study results across a spectrum of human ALD conditions to identify commonalities and translatable mechanisms of ethanol action and putative targets for intervention.