Multiple alpha-fetoprotein RNAs in adult rat liver: cell type-specific expression and differential regulation

Multiple alpha-fetoprotein (AFP) RNAs are expressed in the rat liver and are differentially regulated during development. We examined the expression and cellular distribution of the full-length AFP RNA (major form, 2.1 kilobases highly expressed in fetal liver) and 3 variants of 1.7, 1.4, and 1.0 kilobases in normal rat liver, during fetal development, in regeneration, and in carcinogenesis. The 1.7-kilobase variant is expressed only in developing liver (by 15 days of gestation) and is much less abundant than the major form. In adult normal liver the 1.4- and 1.0-kilobase RNAs are the predominant forms. By cell separation studies we show that these variants are produced by parenchymal and nonparenchymal cells in normal rat liver, and that the full-length AFP mRNA is detectable in normal nonparenchymal cells. We demonstrate by in situ hybridization that the 2.1-kilobase mRNA is expressed by some ductular cells and a few nondividing hepatocytes (approximately 1 in 20,000). Further studies revealed that (a) the 2.1-kilobase AFP mRNA encodes translation products of molecular weight 68,000 and 70,000, and probably has multiple sites for translation initiation; (b) the 1.4-kilobase AFP RNA variant in adult rat liver encodes translation products of molecular weight 58,000, 54,000 and 44,000; (c) the 2.1-kilobase AFP RNA increases in liver nonparenchymal cells after CCl4 injury (20-30-fold) and in galactosamine-injured liver (60-100-fold), while the 1.4- and 1.0-kilobase variants change much less; and (d) after partial hepatectomy there are only small changes in any of the AFP RNAs, while during carcinogenesis oval cells contain large amounts of 2.1-kilobase AFP RNA and levels of the 1.4- and 1.0-kilobase species which are lower than those in normal liver. We suggest that after development synthesis of the full-length RNA is not shut off in a small proportion of rat liver cells and that ductular cells that express this RNA may constitute a facultative liver stem cell compartment.