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Differentiation of Rat Oval Cells after Activation of Peroxisome Proliferator-activated Receptor 43

Merck Research Laboratories, Department of Safety Assessment, Genetic and Cellular Toxicology [C. K., C. J. P., T. G. G., B. J. L.], Chronic Toxicology [T. T. K.], West Point, Pennsylvania 19486

Peroxisome proliferators (PPs) act as nongenotoxic tumor promoters in rodents. Their hepatocarcinogenicity requires the presence of the PP-activated receptor (PPAR); 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 PPAR 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 liver carcinogenesis.

We studied the PPAR-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 rodents) with or without cotreatment with WY14,643, a prototype PPAR-activator. PPAR was expressed at relatively low levels in primary oval cells 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 as well as that of the PPAR-responsive genes encoding fatty acyl-CoA oxidase and cytochrome P450 4A1. Moreover, the oval cell response to WY14,643 was accompanied by an overall phenotypic modulation toward the hepatocyte lineage. In addition, the PPAR activator induced, among the oval cells, a subpopulation of transitional cells showing features of maturing hepatocytes expressing the oncofetal marker, -fetoprotein. These results show that oval cells are responsive to PPs and strongly argue for a role of PPAR 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 markers of mature hepatocytes, consistent with a block during their maturation process, i.e., they are resistant to PPAR-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.

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				B. Knight, B. B. Yeap, G. C. Yeoh, and J. K. Olynyk Inhibition of adult liver progenitor (oval) cell growth and viability by an agonist of the peroxisome proliferator activated receptor (PPAR) family member {gamma}, but not {alpha} or {delta} Carcinogenesis, October 1, 2005; 26(10): 1782 - 1792. [Abstract] [Full Text] [PDF]