Differentiation of rat oval cells after activation of peroxisome proliferator-activated receptor alpha 43

Peroxisome proliferators (PPs) act as nongenotoxic tumor promoters in roden ts, Their hepatocarcinogenicity requires the presence of the PP-activated r eceptor alpha (PPAR alpha); however, the exact role played by this transcri ption factor in the liver, more precisely in liver cell growth and differen tiation, is not known, The aim of this study was to investigate the role of PPAR alpha in oval cells, which are considered to be closely related to li ver stem cells, act as bipotential progenitors for the two main hepatic lin eages, and have been implicated as playing a role in several models of live r carcinogenesis. We studied the PPAR alpha-mediated response of primary oval cells isolated from rats fed a choline-deficient ethionine-supplemented diet (CDE diet, a regimen commonly used for the induction of oval cell proliferation in roden ts) with or without cotreatment with WY14,643, a prototype PPAR alpha-activ ator. PPAR alpha was expressed at relatively low levels in primary oval cel ls from rats fed the CDE diet alone. In vivo treatment with WY14,643 for 2- 6 weeks induced, in the oval cells, the expression of PPAR alpha as well as that of the PPAR alpha-responsive genes encoding fatty acyl-CoA oxidase an d cytochrome P450 4A1, Moreover, the oval cell response to WY14,643 was acc ompanied by an overall phenotypic modulation toward the hepatocyte lineage. In addition, the PPARa activator induced, among the oval cells, a subpopul ation of transitional cells showing features of maturing hepatocytes expres sing the oncofetal marker, alpha-fetoprotein. These results show that oval cells are responsive to PPs and strongly argue for a role of PPAR alpha in the differentiation/maturation of rat oval cells. In the absence of the CDE diet regimen, 9-week treatment with WY14,643 lead to the appearance of a population of large-sized cells somewhat similar to the transitional cells. However, these cells showed little expression of m arkers of mature hepatocytes, consistent with a block during their maturati on process, i.e., they are resistant to PPAR alpha-mediated differentiation . Interestingly, the phenotype of these cells resembled that of the cells u sually found in neoplastic foci induced by PPs, Our results, together with previous reports, suggest the involvement of oval cells in the hepatocarcin ogenicity of PPs.