Role of nuclear receptor-independent pathways in the mechanism of action of peroxisome proliferators Public Deposited

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  • March 22, 2019
  • Woods, Courtney Georgette
    • Affiliation: Gillings School of Global Public Health, Department of Environmental Sciences and Engineering
  • Peroxisome proliferators are a structurally diverse group of chemicals that are non-genotoxic hepatocarcinogens in rodents. For decades there has been controversy surrounding these compounds because of the uncertainty of human risk, high potential for exposure and insufficient understanding of their mechanism of action in rodents. Two key molecular pathways are thought to be important in the mode of action: activation of the nuclear receptor PPARα in liver parenchymal cells, and activation of Kupffer cells, which do not express PPARα. In hepatocytes, PPARα mediates peroxisome induction, increased fatty acid metabolism and alterations in gene expression. Furthermore, activation of the PPARα is required for peroxisome proliferator-induced carcinogenesis. In Kupffer cells, acute administration of peroxisome proliferators stimulates oxidant production and mitogenic cytokine release, as well as activation of NFκB, a transcription factor implicated in cell proliferation and apoptosis. The role that Kupffer cells play in chronic effects of peroxisome proliferators is not yet known. We hypothesized that peroxisome proliferators activate Kupffer cells to produce oxidants that may be involved in oxidative cellular damage, and that mediate cytokine production. The cytokines stimulate proliferative and anti-apoptotic effects of these chemical agents. To test this hypothesis, we first evaluated whether peroxisome proliferators cause a sustained increase in reactive oxygen species (ROS) in rodent liver. In vivo measurements of ROS in PPARα -null or NADPH oxidase-deficient (p47phox-null) mice following sub-acute treatment with di-(2-ethylhexyl) phthalate (DEHP) or 4-chloro-6-(2,3- xylidino)-2-pyrimidinylthio acetic acid (WY-14,643), both model peroxisome proliferators revealed a persistent elevation in oxidant production with parenchymal cells, not Kupffer cells as the primary molecular source. Next, the role of Kupffer cell oxidants and PPARα in mediating proliferative, apoptotic and oxidative stress responses was assessed. Findings from a five month WY-14,643 feeding study suggest that NADPH oxidase is not required for increased hepatocellularl proliferation or DNA damage, but may be important to antiapoptotic effects. Finally, gene expression profiling revealed a temporal shift from Kupffer cell to PPARα-dependence of peroxisome proliferator-induced changes. Collectively, our findings demonstrate that Kupffer cell-mediated events play an important role in early responses, but are short-lived and likely not required for chronic effects of peroxisome proliferators, including hepatocarcinogenesis.
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  • Rusyn, Ivan
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  • University of North Carolina at Chapel Hill
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