MODULATION OF MITOGENESIS BY LIVER FATTY-ACID-BINDING PROTEIN

Liver fatty acid binding protein (L-FABP), a cytoplasmic 14 kDa protein previously termed Z protein, is conventionally considered to be an intracellular carrier of fatty acids in rat hepatocytes. The following evidence now indicates that L-FABP is also a specific mediator of mitogenesis of rat hepatocytes: a. the synergy between the action of L-FABP and unsaturated fatty acids, especially linoleic acid, in the promotion of cell proliferation; b. the specific requirement for L-FABP in induction of mitogenesis by two classes of nongenotoxic hepatocarcinogenic peroxisome proliferators (amphipathic carboxylates and tetrazole-substituted acetophenones); c. the direct correlation between the binding avidities of different prostaglandins for L-FABP and their relative growth inhibitory activities toward cultured rat hepatocytes; d. the temporal coincidences between the covalent binding to L-FABP by chemically reactive metabolites of the genotoxic carcinogens, 2-acetylaminofluorene and aminoazo dyes, and their growth inhibitions of he patocytes during liver carcinogenesis in rats; e and f. the marked elevations of L-FABP in rat liver during mitosis in normal and regenerating hepatocytes, and during the entire cell cycle in the hyperplastic and malignant hepatocytes that are produced by the genotoxic carcinogens, 2-acetylaminofluorene and aminoazo dyes. These actions of L-FABP are consistent with those of a protein involved in regulation of hepatocyte multiplication. Discovery that L-FABP, the target protein of the two types of genotoxic carcinogens, is required for the mitogenesis induced by two classes of nongenotoxic carcinogens points to a common process by which both groups of carcinogens promote hepatocyte multiplication. The implication is that during tumor promotion of liver carcinogenesis, these genotoxic and nongenotoxic carcinogens modify the normal process by which L-FABP, functioning as a specific receptor of unsaturated fatty acids or their metabolites, promotes the multiplication of hepatocytes.