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

Strain CAST/Ei (CAST) mice exhibit unusually low levels of high density lipoproteins (HDL) as compared with most other strains of mice, including C57BL/6J (B6). This appears to be due in part to a functional deficiency of lecithin:cholesterol acyltransferase (LCAT). LCAT mRNA expression in CAST mice is normal, but the mice exhibit several characteristics consistent with functional 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 were relatively poor in phospholipids and cholesteryl esters, but rich in free cholesterol and apoli- poprotein A-I (apoA-I). Third, the adrenals of CAST mice were depleted of cholesteryl esters, a phenotype similar to that observed in LCAT- and acyl-CoA:cholesterol acyltrans- ferase-deficient mice. Fourth, in common with LCAT-deficient mice, CAST mice contained triglyceride-rich lipoproteins with "panhandle"-like protrusions. To examine the genetic bases of these differences, we studied HDL lipid levels in an intercross between strain CAST and the common labora- tory strain B6 on a low fat, chow diet as well as a high fat, atherogenic diet. HDL levels exhibited complex inherit- ance, as 12 quantitative trait loci with significant or sugges- tive likelihood of observed data scores were identified. Sev- eral of the loci occurred over plausible candidate genes and these were investigated. The results indicate that the functional LCAT deficiency is unlikely to be due to varia- tions of the LCAT gene. Our results suggest that novel genes are likely to be important in the control of HDL me- tabolism, and they provide evidence of genetic factors influ- encing the interaction of LCAT with HDL. — Mehrabian, M., L. W. Castellani, P-Z. Wen, J. Wong, T. Rithaporn, S. Y. Hama, G. P. Hough, D. Johnson, J. J. Albers, G. A. Mottino, J. S. Frank, M. Navab, A. M. Fogelman, and A. J. Lusis. Genetic control of HDL levels and composition in an inter- specific mouse cross (CAST/Ei 3 C57BL/6J). J. Lipid Res. 2000. 41: 1936-1946.