Apolipoprotein (apo) A-I production and mRNA abundance explain plasma apoA-I and high density lipoprotein differences between two nonhuman primate species with high and low susceptibilities to diet-induced hypercholesterolemia.

Abstract

Earlier studies have shown that African green monkeys develop a more modest hypercholesterolemia, higher high density lipoprotein (HDL) concentrations, and less atherosclerosis than cynomolgus monkeys fed diets with the same cholesterol content. In the present study, cynomolgus monkeys were fed less cholesterol than was fed to African green monkeys to induce equivalent hypercholesterolemia in both species. African green monkeys still had 2-fold higher plasma HDL cholesterol concentrations and 2.7-fold higher plasma apolipoprotein (apo) A-I concentrations. Therefore, the higher HDL concentration in African green monkeys appears to result from factors that act independently of dietary cholesterol intake or total plasma cholesterol concentration. Two aspects of HDL production were examined to determine the metabolic basis of the species difference in HDL concentration. The rate of hepatic apoA-I secretion, as estimated by the accumulation of apoA-I in the medium during recirculating liver perfusion, was 5-fold higher in livers of African green monkeys. In addition, the concentration of apoA-I mRNA was 2-fold higher in the liver and 3.7-fold higher in the intestine of African green monkeys. Taken together, these findings indicate that differences in apoA-I production in the liver and small intestine are large enough to be responsible for the differences in the plasma concentrations of HDL and apoA-I between these species. Factors which regulate apoA-I secretion, including modulation of tissue apoA-I mRNA concentrations, are important determinants of plasma HDL concentrations and may contribute to the relative resistance of African green monkeys to dietary cholesterol-induced hypercholesterolemia and atherosclerosis. ApoA-I mRNA was also detected at low levels in the kidney and testis of African green and cynomolgus monkeys but not in the adrenal or brain. The tissue distribution and abundance of apoA-I mRNA in peripheral tissues was very different than that seen for apoE mRNA. Kidney and testis apoA-I mRNAs were the same size as liver apoA-I mRNA when examined by Northern blot analysis. Testis apoA-I mRNA appeared to be functionally active as judged by its presence in cytoplasmic polyribosomes. The low levels of apoA-I expression in kidney and testis are unlikely to contribute significantly to the plasma apoA-I pool but might function in some aspect of local lipid metabolism within these tissues.