LIVER FATTY-ACID-BINDING PROTEIN - SPECIFIC MEDIATOR OF THE MITOGENESIS INDUCED BY 2 CLASSES OF CARCINOGENIC PEROXISOME PROLIFERATORS

Peroxisome proliferators (PP) are a diverse group of chemicals that in duce dramatic increases in peroxisomes in rodent hepatocytes, followed by hypertrophy, hepatomegaly, alterations in lipid metabolism, mitoge nesis, and finally hepatocarcinomas. Termed nongenotoxic carcinogens, they do not interact with DNA, are not mutagenic in bacterial assays, and fail to elicit many of the phenotypes associated with classic geno toxic carcinogens. We report here that the mitogenesis induced by the major PP class, the amphipathic carboxylates, and by the tetrazole-sub stituted acetophenones specifically requires liver fatty acid-binding protein (L-FABP) in cultured rat hepatoma cells transfected with the s ense cDNA of L-FABP, in contrast to L-FABP-nonexpressing cells transfe cted with its antisense cDNA. The mitogenic actions of L-FABP were pro tein-specific, inasmuch as no other protein in the nonexpressing cells could act like L-FABP. L-FABP was previously shown not only (i) to in teract covalently with metabolites of the two genotoxic carcinogens 2- acetylaminofluorene and aminoazo dyes during liver carcinogenesis, but also (ii) to bind noncovalently the two classes of PP in vitro with a vidities that correlate with their abilities to elicit peroxisomal enz ymatic responses, and (iii) together with unsaturated fatty acids, esp ecially linoleic acid, to promote multiplication of the transfected he patoma cells in culture. The convergence of the two types of genotoxic carcinogens with the two classes of PP nongenotoxic carcinogens, and also with unsaturated fatty acids, at L-FABP actions in inducing mitog enesis allows the following hypothesis. During tumor promotion of carc inogenesis in vivo, these groups of genotoxic and nongenotoxic carcino gens act on the normal process by which L-FABP, functioning as a speci fic receptor of unsaturated fatty acids or their metabolites, promotes hepatocyte proliferation.