Hyper- and hypo-responsiveness to dietary fat and cholesterol among inbred mice: searching for level and variability genes.

A concept proposed by Berg (Berg, K. 1989. Arteriosclerosis. 9: I-50-I-58) is that a combination of level and variability genes determine an individual's overall plasma lipid levels and atherosclerotic risk. Our goal was to determine which inbred mouse strains could be used to identify candidate level and variability genes controlling lipid levels and atherosclerosis susceptibility. Nine common inbred mouse strains were examined for responsiveness with respect to plasma lipoprotein and tissue lipid levels upon feeding diets rich in cholesterol and fat. Marked quantitative variations were observed in plasma cholesterol and triglyceride levels among mice fed rodent chow and the high fat test diets. Mice of strains DBA/2 and AKR appeared to be hyporesponsive to diets containing high levels of fat and cholesterol as compared to rodent chow. In contrast, several strains were primarily hyperresponsive to either dietary fat or cholesterol, or both ingredients. Determination of cholesterol absorption for selected strains fed test diets suggested that decreased cholesterol absorption, in part, contributes to hyporesponsiveness as seen in DBA/2 mice. Levels of mRNA for cholesterol 7 alpha-hydroxylase were estimated and shown to vary markedly among strains. An inverse correlation was seen among strains between cholesterol 7 alpha-hydroxylase mRNA, and plasma and hepatic cholesterol levels for some diets. Thus, genes controlling cholesterol absorption and bile acid synthesis are candidates for further study as level and variability genes affecting plasma cholesterol levels. Overall, inbred mouse strains will prove useful for identifying genes controlling level and variability traits.