Genetic control of hepatic apoB-100 secretion in human apoB transgenic mouse strains.
Plasma apolipoprotein B (apoB) levels vary widely in the general population and elevated plasma levels of apoB are associated with higher risk for atherosclerotic coronary heart disease. Determination of genetic factors regulating population variance of plasma apoB levels is complicated by the genetic heterogeneity of human populations. Using a congenic human apoB transgenic mouse strain in the C57BL/6 background (B6 HuBTg), we assessed genetic effects on the variance of plasma apoB, and on hepatic apoB-100 secretion rates. Six inbred mouse strains were crossed with the B6 HuBTg strain. Mean plasma apoB levels in the parental B6 HuBTg strain were 95 +/- 14 mg/dl. F1 human apoB transgenic offspring displayed plasma human apoB levels ranging from 60 to 105 mg/dl. In three F1 strains, the BALB/B6, C3H/B6 and 129/B6 strains, markedly lower plasma apoB levels (61 +/- 11, 64 +/- 5, and 67 +/- 8 mg/dl) were due to lower apoB-100 secretion rates. Human apoB mRNA levels in these three F1 strains were similar to those of the parental B6 strain suggesting that the mechanism for varying apoB secretion rates is most likely not transcriptional. In summary, we have identified three inbred mouse strains possessing polymorphic alleles which, when crossed with the B6 strain, lower plasma apoB levels and apoB-100 secretion in their F1 offspring. These mouse strains provide a powerful tool for genetic analysis of factors regulating apoB-100 secretion and hence plasma apoB levels.