Linkage, evolution, and expression of the rat apolipoprotein A-I, C-III, and A-IV genes.

The genes coding for three of the proteins of the lipid transport system, apolipoproteins A-I (apoA-I), C-III (apoC-III), and A-IV (apoA-IV), are closely linked and tandemly organized as a multigene family in the human genome. The evolution of this multigene family was studied by cloning and extensive restriction mapping analysis of an approximately 20-kilobase genomic DNA fragment containing the rat apoA-I gene. Low stringency hybridization blotting analysis of this DNA fragment using human apoC-III and apoA-IV cDNA probes revealed that the apoA-I, apoC-III, and apoA-IV genes are also closely linked and tandemly organized in the rat genome. Complete characterization of the rat apoA-I, apoC-III, and apoA-IV genes showed that their relative location, size, direction of transcription, and intron-exon organization are remarkably similar to those of the corresponding human genes. The relative steady state apoA-I, apoC-III, and apoA-IV mRNA levels in various rat tissues were determined by quantitative dot blot hybridization of tissue total RNA using the corresponding gene probes. Adult liver and intestine, but not colon, brain, spleen, muscle, heart, lung, and kidney, contain apoA-I, apoC-III, and apoA-IV mRNAs. Fetal liver and intestine contain apoA-I but not apoC-III or apoA-IV mRNAs. During neonatal development the liver contains apoA-I and apoC-III but not apoA-IV while the intestine contains apoA-I, apoC-III, and substantial amounts of apoA-IV mRNAs. In adulthood and during aging both liver and intestine contain all three apoA-I, apoC-III, and apoA-IV mRNAs. These results indicate that the apolipoprotein A-I/C-III/A-IV multigene family was established before mammalian radiation and suggest that these genes are similarly organized in the genomes of all mammals. In addition, these results indicate that expression of the rat apoA-I, apoC-III, and apoA-IV genes is liver- and intestine-specific and regulated by fetal-, neonatal-, and aging-related factors.