Genetic control of HDL levels and composition in an interspecific mouse cross (CAST/Ei x C57BL/6J)

Strain CAST/Ei (CAST) mice exhibit unusually low levels of high density lip oproteins (HDL) as compared with most other strains of mice, including C57B L/6J (B6). This appears to be due in part to a functional deficiency of lec ithin:cholesterol acyltransferase (LCAT). LCAT mRNA expression in CAST mice is normal, but the mice exhibit several characteristics consistent with fu nctional deficiency. First, the activity and mass of LCAT in plasma and in HDL of CAST mice were reduced significantly. Second, the HDL of CAST mice w ere relatively poor in phospholipids and cholesteryl esters, but rich in fr ee cholesterol and apolipoprotein A-I (apoA-I). Third, the adrenals of CAST mice were depleted of cholesteryl esters, a phenotype similar to that obse rved in LCAT- and acyl-CoA:cholesterol acyltransferase-deficient mice. Four th, in common with LCAT-deficient mice, CAST mice contained triglyceride-ri ch lipoproteins with "panhandle"-like protrusions. To examine the genetic b ases of these differences, we studied HDL lipid levels in an intercross bet ween strain CAST and the common laboratory strain B6 on a low fat, chow die t as well as a high fat, atherogenic diet. HDL levels exhibited complex inh eritance, as 12 quantitative trait loci with significant or suggestive like lihood of observed data scores were identified. Several of the loci occurre d over plausible candidate genes and these were investigated. The results i ndicate that the functional LCAT deficiency is unlikely to be due to variat ions of the LCAT gene. Our results suggest that novel genes are Likely to b e important in the control of HDL metabolism, and they provide evidence of genetic factors influencing the interaction of LCAT with HDL.