Peroxisome proliferators include a broad spectrum of structurally diverse synthetic and naturally occurring compounds of biological interest. They induce qualitatively predictable immediate and delayed pleiotropic responses, including the development of hepatocellular carcinomas in rats and mice. Peroxisome proliferators are nonmutagenic in that they do not directly damage DNA, thereby leading to our hypothesis that the development of liver tumors is attributable to sustained activation of a cell-specific receptor and ensuing metabolic perturbations. The cloning of peroxisome proliferator-activated receptor (PPAR) subfamily of nuclear receptors has firmly affirmed the receptor concept we proposed and now sets the stage to explore molecular mechanisms that determine the cell, species and gene specific responses. Our current emphasis is based on the hypothesis that biochemical and metabolic perturbations occurring in liver as a result of activation of PPARs, in particular PPARalpha and PPARgamma, are responsible for alterations in hepatocellular function and their proliferative potential. Identification and characterization of PPARalpha and PPARgamma target genes in liver should focus on the hepatocentric nature of PPARalpha and PPARgamma related energy metabolism and their effects on steatohepatitis and hepatocellular carcinoma development.
Our specific aims are to: 1) Investigate, by using comparative functional oncogenomics, the expression signature and molecular pathways characteristic for PPARalpha by analyzing sequential and progressive changes in gene expression and phenotypic patterns from early lesions to fully developed hepatocellular carcinomas in mice with sustained PPARalpha activation; 2) Explore the role of H2O2-generating oxidases, in particular the role of human fatty acyl-CoA oxidase (AOX) gene, hepatocellular proliferation and steatohepatitis in liver carcinogenesis by analyzing gene knockout mice and by generating humanized transgenic mice with BAC human AOX clone in mouse AOX null background; 3) To generate """"""""proteomic portraits"""""""" of PPARalpha-interacting cofactor (PRIC) complex using rat liver nuclear extracts, identify and characterize some novel components and use this proteomic portrait as a prototype to evaluate the compositional differences in responsive and non-responsive tissues and species; and 4) Identify PPARgamma induced genes in liver and characterize the functions of selected genes, especially that of promethin and PGLP, which we recently cloned, in PPARgamma-induced hepatic adiposis and in PPARalpha-induced phenotypic changes in liver, including liver cancer if any. The studies we now propose will generate new information, which can provide insights into the molecular complexity and the functional implications of PPAR regulated gene expression in liver.
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