Peroxisome proliferators (PPs) are a diverse group of nongenotoxic chemicals that in rodents cause hepatic peroxisome proliferation, liver enlargement, increased replicative DNA synthesis and suppression of apoptosis. The effects of PPs in vivo can be reproduced in vitro where PPs can induce mouse hepatocyte DNA synthesis and suppress both spontaneous apoptosis and that induced by transforming growth factor β (TGFβ). In vitro, high concentrations (>500 U/ml) of exogenous tumour necrosis factor α (TNFα) [M. Rolfe, N.H. James, R.A. Roberts, TNFα suppresses apoptosis and induces S-phase in rodent hepatocytes: a mediator of the hepatocarcinogenicity of peroxisome proliferators?, Carcinogenesis 18 (1997) 2277-2280] are also able to stimulate hepatocyte DNA synthesis and suppress apoptosis, implicating TNFα in mediating or permitting the liver growth response to PPs. Here, using cultured mouse hepatocytes isolated from PPARα null mice, we have examined the role of the peroxisome proliferator activated receptor α (PPARα) in mediating the suppression of apoptosis caused by PPs. In addition we have investigated further the role of TNFα in mediating the rodent response to PPs. The PP nafenopin (50 μM) was unable to stimulate DNA synthesis measured by bromodeoxyuridine incorporation in these PPARα null mouse hepatocytes (96% of control), unlike epidermal growth factor, a growth factor used as a positive control. In assays of apoptosis using H33258 staining of chromatin condensation, nafenopin was unable to suppress either spontaneous or TGFβ1-induced apoptosis. In contrast, high concentrations of TNFα (>500 U/ml) were able to both stimulate DNA synthesis (204% of control) and suppress apoptosis in PPARα null hepatocytes (40% and 38% of control for spontaneous and TGFβ1-induced apoptosis respectively). However, TNFα could not stimulate β-oxidation of palmitoyl CoA in either PPARα null mouse or B6C3F1 (PPARα wild type) mouse hepatocytes. These data confirm the dependence of the response to PPs on PPARα by demonstrating that PPARα mediates the suppression of hepatocyte apoptosis in response to PPs. In addition, the data provide evidence that high concentrations of TNFα can modulate DNA synthesis and apoptosis in the absence of PPs and PPARα. Thus, in vivo, physiological levels of TNFα may be permissive for a PPARα-dependent growth response to PPs. Copyright (C) 2000 Elsevier Science B.V.
|Original language||English (US)|
|Number of pages||8|
|Journal||Mutation Research - Fundamental and Molecular Mechanisms of Mutagenesis|
|State||Published - Mar 17 2000|
All Science Journal Classification (ASJC) codes
- Molecular Biology
- Health, Toxicology and Mutagenesis