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Abstract
Peroxisome proliferators (PPs) are rodent nongenotoxic hepatocarcinogens that induce peroxisome proliferation and DNA synthesis, and suppress apoptosis in rodent hepatocytes. PPs act through the PP-activated receptor α (PPARα); tumour necrosis factor α (TNFα) and hepatic nonparenchymal cells (NPCs), the major source of TNF α in the liver, have also been implicated in mediating the rodent hepatic response to PPs. Here we investigate the interaction between PPARα and NPCs in regulating the response to PPs. Using normal hepatocyte cultures containing around 20% NPCs, the PP nafenopin (50 µM) induced DNA synthesis and suppressed transforming growth factor β^sub 1^-induced apoptosis. However, when the NPCs were removed by differential centrifugation, nafenopin did not induce DNA synthesis or suppress apoptosis in the pure hepatocytes. Reconstitution of the normal hepatocyte cultures by mixing together the pure hepatocytes and the previously separated NPCs in the same proportions as the original cell preparation (17.7±8.7% NPCs) restored the response to nafenopin. Interestingly, nafenopin was still able to induce β-oxidation in the pure hepatocyte cultures, consistent with NPCs being required for PP-induced growth but not for peroxisome proliferation. Next, we evaluated the role of PPARα in the hepatocyte dependency upon NPCs. Interestingly, NPCs isolated from PPARα-null mice, like those isolated from the wild-type NPCs, restored the hepatocyte response to nafenopin. However, as expected, PPARα-null hepatocytes remained non-responsive to PPs, irrespective of the genotype of the added NPCs. These data support a role for NPCs in facilitating a response of hepatocytes to PPs that is ultimately dependent on the presence of PPARα in the hepatocyte.[PUBLICATION ABSTRACT]