Thesis supervisor: Gyöngyi Szabó
Location of studies (in Hungarian): USA Abbreviation of location of studies: USA
Description of the research topic:
Description: Alcoholic liver disease begins with fat accumulation (steatosis) and inflammatory changes and often progresses to fibrosis and cirrhosis; the latter predisposes to the development of hepatocellular carcinoma. This project will extend earlier studies supporting a role for hypoxia-inducible factors (HIFs) in the pathogenesis of alcoholic liver disease. HIFs are heterodimeric transcription factors that regulate the cellular response to tissue hypoxia and are overexpressed in many human cancers. Under hypoxia, HIF activates the transcription of a range of downstream targets, including glycolytic enzymes and pro-angiogenic hormones, as well as proteins that have been implicated in steatosis. Thus, we hypothesize that HIF activation underlies the steatotic change seen in the livers of chronically alcohol-fed mice via regulation of a number of downstream target genes. We utilize a mouse model of constitutive, hepatocyte-specific HIF activation to determine whether alcohol-mediated liver injury can be accelerated via this pathway. Increasing evidence suggests that HIF can be activated independent of hypoxia via reactive oxygen radicals. ROS generation by the NADPH oxidase complex is a major consequence of chronic alcohol use in alcoholic liver disease. We postulate that HIF activation in alcoholic liver disease is mediated via ROS generation from NADPH oxidases. Lastly, we propose that these events may be differentially regulated in hepatocytes and Kupffer cells and/or inflammatory cells in the liver. These hypotheses will be tested in the following Specific Aims:
Aim 1. To evaluate and compare the role of HIF1 and HIF2 in the pathogenesis of alcoholic steatosis by investigating HIF1alpha and/or HIF2alpha protein and mRNA and whether those changes correlate positively to active HIF1 or HIF2 transcription factor activity; and whether constitutively active HIF1 expressed in hepatocytes has an accelerating effect on the pathogenesis of chronic alcohol-mediated liver disease, using a hepatocyte-specific HIF1 transgenic mouse model.
Aim 2. To investigate the effect of NADPH oxidases and the cell-specificity in HIF activation in alcohol-induced liver injury by investigating the expression and activity of the components of NADPH oxidase complex in the liver after alcohol feeding in control and hepatocyte-specific HIF-1 transgenic mice; testing the effect of alcohol feeding in p47phox deficient mice on steatosis and HIF activation; dissecting the effect of NADPH oxidase activation by alcohol feeding between hepatocytes and immune cells in bone marrow chimeras generated between p47phox and wild-type mice.
Results from these experiments will define the role of hypoxia-inducible factors in the pathogenesis of alcoholic liver steatosis and inflammation. Moreover, we will explore novel mechanisms that may link alcohol-induced reactive oxygen radical production by NADPH oxidases to activation of HIF and steatotic liver injury.
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