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.
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 [poE(-/-); 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.
Ishibashi
S
S
Department of Molecular Genetics, University of Texas Southwestern Medical Center, Dallas 75235-9046.
Herz
J
J
Maeda
N
N
Goldstein
J L
JL
Brown
M S
MS
D000818:Animals; D001057:Apolipoproteins E / Q000172:deficiency / Q000235:genetics*; D002784:Cholesterol / Q000097:blood*; D002791:Cholesterol, Dietary; D003433:Crosses, Genetic; D004032:Diet; D005260:Female; D005838:Genotype; D006720:Homozygote; D008074:Lipoproteins / Q000097:blood*; D008297:Male; D051379:Mice; D008817:Mice, Mutant Strains; D008954:Models, Biological; D011973:Receptors, LDL / Q000172:deficiency / Q000235:genetics*
D001057:Apolipoproteins E; D002791:Cholesterol, Dietary; D008074:Lipoproteins; D011973:Receptors, LDL; D002784:Cholesterol