COMPLEX GENETIC-CONTROL OF HDL LEVELS IN MICE IN RESPONSE TO AN ATHEROGENIC DIET - COORDINATE REGULATION OF HDL LEVELS AND BILE-ACID METABOLISM

Inbred strains of mice differ in susceptibility to atherogenesis when challenged with a high fat, high cholesterol diet containing 0.5% chol ic acid. Studies of recombinant inbred (RI) strains derived from the s usceptible strain C57BL/6J (B6) and the resistant strains C3H/HeJ (C3H ) and BALB/cJ have revealed an association between fatty streak lesion size and a decrease in high density lipoprotein (HDL) levels on the d iet. To better understand the genetic factors contributing to HDL meta bolism and atherogenesis in response to the diet, we studied mice deri ved from an intercross between B6 and C3H using a complete linkage map approach. A total of 185 female progeny were typed for 134 genetic ma rkers spanning the mouse genome, resulting in an average interval of a bout 10 cM between markers. A locus on distal chromosome 1 containing the apolipoprotein AII gene was linked to HDL-cholesterol levels on bo th the chow and the atherogenic diets, but this locus did not contribu te to the decrease in HDL-cholesterol in response to the diet, At leas t three distinct genetic loci, on chromosomes 3, 5, and 11, exhibited evidence of linkage to a decrease in HDL-cholesterol after a dietary c hallenge, Since a bile acid (cholic acid) is required for the diet ind uced changes in HDL levels and for atherogenesis in these strains, we examined cholesterol-7-alpha hydroxylase (C7AH) expression. Whereas B6 mice exhibited a large decrease in C7AH mRNA levels in response to th e diet, C3H showed an increase, Among the intercross mice, multiple lo ci contributed to the regulation of C7AH mRNA levels in response to th e diet, the most notable of which coincided with the loci on chromosom es 3, 5, and 11 controlling HDL levels in response to the diet. None o f these loci were linked to the C7AH structural gene which we mapped t o proximal chromosome 4, These studies reveal coordinate regulation of C7AH expression and HDL levels, and they indicate that the genetic fa ctors controlling HDL levels are more complex than previously suggeste d by studies of RI strains, Furthermore, we observed that two of the l oci for C7AH expression contributed to differences in gallstone format ion between these strains.