Comprehensive QTL analysis of serum cholesterol levels before and after a high-cholesterol diet in SHRSP

Abstract

The stroke-prone spontaneously hypertensive rat (SHRSP) showed an exaggerated response to a high-fat, high-cholesterol (HFC) diet, and the resulting reactive hypercholesterolemia was suggested to exacerbate the atherogenic process in this rat. We thus performed a quantitative trait locus (QTL) analysis on the serum cholesterol level of SHRSP before and after the HFC diet, with the final goal being the identification of the genetic mechanisms of its reactive hypercholesterolemia. Three hundred fifty-eight F2 rats between SHRSP and Wistar-Kyoto rat were employed in the study. The serum cholesterol and apoprotein E were measured before and after 2 wk of feeding with the HFC diet. Multiple QTLs for the basal cholesterol level were identified on chromosomes 1 and 5, whereas those for the postdietary cholesterol level were on chromosomes 7, 15, and 16. The cholesterol QTLs before and after HFC diet did not overlap with one another, implying that the involved metabolic processes were considerably different between the two conditions. Supporting this, VLDL and LDL cholesterol were the major components of the postdietary serum cholesterol, whereas the basal cholesterol level consisted mainly of HDL cholesterol. A substantial difference of the QTLs between males and females was observed, especially after the HFC diet. The QTL on chromosome 15 had an inverse effect on the cholesterol level, suggesting that the congenic substitution of the SHRSP fragment with that of Wistar-Kyoto rats could induce a greater cholesterol level in SHRSP. This observation is significant in establishing a new model for atherosclerosis with hypertension in rats.