The two-receptor model of lipoprotein clearance: Tests of the hypothesis in 'knockout' mice lacking the low density lipoprotein receptor, apolipoprotein E, or both proteins

Shun Ishibashi, Joachim Herz, Nobuyo Maeda, Joseph L. Goldstein, Michael S. Brown

Research output: Contribution to journalArticle

340 Scopus citations

Abstract

Apolipoprotein E (apoE) is hypothesized to mediate lipoprotein clearance by binding to two receptors: (i) the low density lipoprotein receptor (LDLR) and (ii) a chylomicron remnant receptor. To test this hypothesis, we have compared plasma lipoproteins in mice that are homozygous for targeted disruptions of the genes for apoE [apoE(-/-)], the LDLR [LDLR(-/-)], and both molecules [apoE(-/-); LDLR(-/-)]. On a normal chow diet, apoE(-/-) mice had higher mean plasma cholesterol levels than LDLR(-/-) mice (579 vs. 268 mg/dl). Cholesterol levels in the apoE(-/-); LDLR(-/-) mice were not significantly different from those in the apoE(-/-) mice. LDLR(-/-) mice had a relatively isolated elevation in plasma LDL, whereas apoE(-/-) mice had a marked increase in larger lipoproteins corresponding to very low density lipoproteins and chylomicron remnants. The lipoprotein pattern in apoE(-/-); LDLR(-/-) mice resembled that of apoE(-/-) mice. The LDLR(-/-) mice had a marked elevation in apoB-100 and a modest increase in apoB-48. In contrast, the apoE(-/-) mice had a marked elevation in apoB-48 but not in apoB-100. The LDLR(-/-); apoE(-/-) double homozygotes had marked elevations of both apolipoproteins. The observation that apoB-48 increases more dramatically with apoE deficiency than with LDLR deficiency supports the notion that apoE binds to a second receptor in addition to the LDLR. This conclusion is also supported by the observation that superimposition of a LDLR deficiency onto an apoE deficiency [apoE(-/-); LDLR(-/-) double homozygotes] does not increase hypercholesterolemia beyond the level observed with apoE deficiency alone.

Original languageEnglish (US)
Pages (from-to)4431-4435
Number of pages5
JournalProceedings of the National Academy of Sciences of the United States of America
Volume91
Issue number10
DOIs
StatePublished - 1994

Keywords

  • atherosclerosis
  • chylomicrons
  • gene targeting
  • hypercholesterolemia
  • very low density lipoproteins

ASJC Scopus subject areas

  • General

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