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

M. Mehrabian, L. W. Castellani, P. Z. Wen, J. Wong, T. Rithaporn, S. Y. Hama, G. P. Hough, David G Johnson, J. J. Albers, G. A. Mottino, J. S. Frank, M. Navab, A. M. Fogelman, A. J. Lusis

Research output: Contribution to journalArticle

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Abstract

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 apolipoprotein 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 acyltransferase-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 laboratory strain B6 on a low fat, chow diet as well as a high fat, atherogenic diet. HDL levels exhibited complex inheritance, as 12 quantitative trait loci with significant or suggestive likelihood of observed data scores were identified. Several 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 variations of the LCAT gene. Our results suggest that novel genes are likely to be important in the control of HDL metabolism, and they provide evidence of genetic factors influencing the interaction of LCAT with HDL.

Original languageEnglish (US)
Pages (from-to)1936-1946
Number of pages11
JournalJournal of Lipid Research
Volume41
Issue number12
StatePublished - 2000
Externally publishedYes

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Phosphatidylcholine-Sterol O-Acyltransferase
HDL Lipoproteins
Chemical analysis
Lecithin Cholesterol Acyltransferase Deficiency
Genes
Cholesterol Esters
Nutrition
Fats
Sterol O-Acyltransferase
Atherogenic Diet
Apolipoprotein A-I
Fat-Restricted Diet
Quantitative Trait Loci
Metabolism
High Fat Diet
Lipoproteins
Inbred C57BL Mouse
Phospholipids
Triglycerides
Cholesterol

Keywords

  • Adrenal lipid depletion
  • Apolipoprotein A-I
  • Cholesterol-7α-hydroxylase
  • High fat diet
  • Lecithin:cholesterol acyltransferase
  • Phospholipid transfer protein
  • Quantitative trait locus mapping
  • Scavenger receptor BI

ASJC Scopus subject areas

  • Endocrinology

Cite this

Mehrabian, M., Castellani, L. W., Wen, P. Z., Wong, J., Rithaporn, T., Hama, S. Y., ... Lusis, A. J. (2000). Genetic control of HDL levels and composition in an interspecific mouse cross (CAST/Ei × C57BL/6J). Journal of Lipid Research, 41(12), 1936-1946.

Genetic control of HDL levels and composition in an interspecific mouse cross (CAST/Ei × C57BL/6J). / Mehrabian, M.; Castellani, L. W.; Wen, P. Z.; Wong, J.; Rithaporn, T.; Hama, S. Y.; Hough, G. P.; Johnson, David G; Albers, J. J.; Mottino, G. A.; Frank, J. S.; Navab, M.; Fogelman, A. M.; Lusis, A. J.

In: Journal of Lipid Research, Vol. 41, No. 12, 2000, p. 1936-1946.

Research output: Contribution to journalArticle

Mehrabian, M, Castellani, LW, Wen, PZ, Wong, J, Rithaporn, T, Hama, SY, Hough, GP, Johnson, DG, Albers, JJ, Mottino, GA, Frank, JS, Navab, M, Fogelman, AM & Lusis, AJ 2000, 'Genetic control of HDL levels and composition in an interspecific mouse cross (CAST/Ei × C57BL/6J)', Journal of Lipid Research, vol. 41, no. 12, pp. 1936-1946.
Mehrabian M, Castellani LW, Wen PZ, Wong J, Rithaporn T, Hama SY et al. Genetic control of HDL levels and composition in an interspecific mouse cross (CAST/Ei × C57BL/6J). Journal of Lipid Research. 2000;41(12):1936-1946.
Mehrabian, M. ; Castellani, L. W. ; Wen, P. Z. ; Wong, J. ; Rithaporn, T. ; Hama, S. Y. ; Hough, G. P. ; Johnson, David G ; Albers, J. J. ; Mottino, G. A. ; Frank, J. S. ; Navab, M. ; Fogelman, A. M. ; Lusis, A. J. / Genetic control of HDL levels and composition in an interspecific mouse cross (CAST/Ei × C57BL/6J). In: Journal of Lipid Research. 2000 ; Vol. 41, No. 12. pp. 1936-1946.
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AU - Mehrabian, M.

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AU - Wen, P. Z.

AU - Wong, J.

AU - Rithaporn, T.

AU - Hama, S. Y.

AU - Hough, G. P.

AU - Johnson, David G

AU - Albers, J. J.

AU - Mottino, G. A.

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N2 - 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 apolipoprotein 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 acyltransferase-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 laboratory strain B6 on a low fat, chow diet as well as a high fat, atherogenic diet. HDL levels exhibited complex inheritance, as 12 quantitative trait loci with significant or suggestive likelihood of observed data scores were identified. Several 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 variations of the LCAT gene. Our results suggest that novel genes are likely to be important in the control of HDL metabolism, and they provide evidence of genetic factors influencing the interaction of LCAT with HDL.

AB - 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 apolipoprotein 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 acyltransferase-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 laboratory strain B6 on a low fat, chow diet as well as a high fat, atherogenic diet. HDL levels exhibited complex inheritance, as 12 quantitative trait loci with significant or suggestive likelihood of observed data scores were identified. Several 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 variations of the LCAT gene. Our results suggest that novel genes are likely to be important in the control of HDL metabolism, and they provide evidence of genetic factors influencing the interaction of LCAT with HDL.

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KW - Scavenger receptor BI

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