Altered lipoprotein metabolism in transgenic mice expressing low levels of a human receptor-binding-defective apolipoprotein E variant

Sergio Fazio, Y. Horie, W. S. Simonet, K. H. Weisgraber, J. M. Taylor, S. C. Rall

Research output: Contribution to journalArticle

17 Citations (Scopus)

Abstract

Transgenic mouse lines were produced that expressed low levels of a receptor-binding-defective variant of human apolipoprotein (apo) E, apoE(Arg112, Cys142). In transgenic mice, the human apoE was produced only by the kidney, whereas endogenous mouse apoE was produced mainly by the liver. The plasma concentration of the transgenic protein was about half that of endogenous apoE. The expression of transgenic apoE did not affect total plasma cholesterol and triglyceride levels, but the distribution of the human variant differed from that of endogenous apoE in the intermediate size and density range, where the transgenic protein accumulated selectively. Immunoblots of agarose gels of lipoprotein fractions showed that the transgenic protein occurred primarily on large α-migrating particles (HDL1). This phenomenon was not observed in transgenic mice expressing normal human apoE-3, which distributed like endogenous apoE, suggesting that the defective apoE variant perturbed HDL1 metabolism. In mice fed a high- fat, high-cholesterol diet, the transgenic apoE associated primarily with the apoB-containing lipoproteins. A significantly higher increase in very low density lipoprotein cholesterol was observed in fat-fed transgenics compared to fat-fed nontransgenic mice, suggesting a metabolic perturbation of apoB- containing lipoproteins. Thus, the receptor-binding-defective variant, apoE(Arg112, Cys142), expressed at low levels by the kidney, alters lipoprotein metabolism in transgenic mice, presumably by interfering with apoE-mediated removal of the lipoproteins from circulation.

Original languageEnglish (US)
Pages (from-to)408-416
Number of pages9
JournalJournal of Lipid Research
Volume35
Issue number3
StatePublished - 1994
Externally publishedYes

Fingerprint

Apolipoproteins E
Metabolism
Transgenic Mice
Lipoproteins
Fats
Apolipoproteins B
Cholesterol
Kidney
Plasmas
VLDL Cholesterol
Proteins
High Fat Diet
Nutrition
Liver
Sepharose
Triglycerides
Gels

Keywords

  • dysbetalipoproteinemia
  • hyperlipoproteinemia
  • lipoprotein metabolism

ASJC Scopus subject areas

  • Endocrinology

Cite this

Altered lipoprotein metabolism in transgenic mice expressing low levels of a human receptor-binding-defective apolipoprotein E variant. / Fazio, Sergio; Horie, Y.; Simonet, W. S.; Weisgraber, K. H.; Taylor, J. M.; Rall, S. C.

In: Journal of Lipid Research, Vol. 35, No. 3, 1994, p. 408-416.

Research output: Contribution to journalArticle

Fazio, Sergio ; Horie, Y. ; Simonet, W. S. ; Weisgraber, K. H. ; Taylor, J. M. ; Rall, S. C. / Altered lipoprotein metabolism in transgenic mice expressing low levels of a human receptor-binding-defective apolipoprotein E variant. In: Journal of Lipid Research. 1994 ; Vol. 35, No. 3. pp. 408-416.
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