Differentiation of XXXX oval cells after activation of peroxisome proliferator-activated receptor alpha43.

@entity3725 @entity12074 @entity5 @entity409 @entity48194 @entity1877 @entity10452 @entity8595 @entity35 @entity21372
Peroxisome proliferators (PPs) act as @entity5 promoters in rodents. Their hepatocarcinogenicity requires the presence of the PP-activated receptor alpha ( @entity3725 ); however, the exact role played by this transcription factor in the liver, more precisely in liver cell growth and differentiation, is not known. The aim of this study was to investigate the role of @entity3725 in oval cells, which are considered to be closely related to liver stem cells, act as bipotential progenitors for the two main hepatic lineages, and have been implicated as playing a role in several models of @entity409 . We studied the @entity3725 -mediated response of primary oval cells isolated from @entity35 fed a @entity1877 -deficient @entity10452 -supplemented diet (CDE diet, a regimen commonly used for the induction of oval cell proliferation in rodents) with or without cotreatment with @entity21372 , a prototype @entity3725 -activator. @entity3725 was expressed at relatively low levels in primary oval cells from @entity35 fed the CDE diet alone. In vivo treatment with @entity21372 for 2-6 weeks induced, in the oval cells, the expression of @entity3725 as well as that of the @entity3725 -responsive genes encoding fatty @entity8595 oxidase and @entity48194 . Moreover, the oval cell response to @entity21372 was accompanied by an overall phenotypic modulation toward the hepatocyte lineage. In addition, the @entity3725 activator induced, among the oval cells, a subpopulation of transitional cells showing features of maturing hepatocytes expressing the oncofetal marker, @entity12074 . These results show that oval cells are responsive to PPs and strongly argue for a role of @entity3725 in the differentiation/maturation of @entity35 oval cells. In the absence of the CDE diet regimen, 9-week treatment with @entity21372 lead to the appearance of a population of large-sized cells somewhat similar to the transitional cells. However, these cells showed little expression of markers of mature hepatocytes, consistent with a block during their maturation process, i.e., they are resistant to @entity3725 -mediated differentiation. Interestingly, the phenotype of these cells resembled that of the cells usually found in neoplastic foci induced by PPs. Our results, together with previous reports, suggest the involvement of oval cells in the hepatocarcinogenicity of PPs.
