Rat apolipoproteins (apo-) A-IV and A-I share many structural similarities, the most notable of which is a domain of repeated docosapeptides with amphipathic helical potential. Although the genes for apo-A-IV and apo-A-I probably diverged from a common ancestor, these proteins seem to have developed different functions in their evolution. In the present study, cloned cDNAs were used to characterize the expression of apo-A-IV and apo-A-I mRNAs in a wide variety of adult rat tissues, as well as in small intestine and liver obtained from fetal, suckling, and weanling animals; comparisons were made to the expression of apo-E mRNA. The apo-A-IV and apo-A-I mRNAs were most abundant in adult small intestine and liver, with trace amounts detected in other tissues. Substantial amounts of these mRNAs were detected in the yolk sac, suggesting that this fetal tissue plays an important role in lipid metabolism during gestation. Noncoordinate accumulation of apo-A-IV and apo-A-I mRNAs was observed within and between the liver and small intestine during neonatal development. The apo-A-IV mRNA levels in the developing small intestine and liver appeared to correlate with their triglyceride secretion rates, suggesting that this protein plays an important role in the metabolism of triglyceride-rich lipoproteins. When dexamethasone (0.1 microM), insulin (0.01 microM), or insulin and dexamethasone together were incubated with primary cultures of nonproliferating adult rat hepatocytes, apo-A-IV mRNA levels were 4-, 7-, and 11-fold higher, respectively, than in non-hormone-treated control hepatocytes. Hormone administration resulted in a 2-fold greater amount of apo-A-I mRNA in each case, with no significant change in the level of apo-E mRNA. The overall results suggest that these structurally related apolipoproteins are regulated in substantially different ways.