Isoprotein specificity in the hepatic uptake of apolipoprotein E and the pathogenesis of familial dysbetalipoproteinemia.

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Abstract
The uptake and catabolism of lamellar complexes of rat 125I-labeled apolipoprotein (apo) E with egg lecithin were increased severalfold in perfused livers of rats given large amounts of 17.alpha.-ethynylestradiol for 5 days. Estrogen-stimulated uptake of lamellar complexes of human apo E that contained all of the major normally occurring isoforms of the protein (apo E-1, E-2, E-3 and E-4) was comparable to that of rat apo E. Uptake of complexes containing apo E from individuals with familial dysbetalipoproteinemia (dys.beta.LP; characterized by a lack of apo E-3 and E-4) was stimulated to a much lesser extent. With complexes containing individual isoforms of human apo E, estrogen-stimulated hepatic uptake was largely confined to apo E-3 and E-4; uptake of apo E-2 from normolipoproteinemic or dys.beta.LP individuals, or of apo E-1 from the latter, was stimulated little or not at all. When considered in the light of available information about the hepatic uptake of lipoproteins and the metabolic defect in familial dys.beta.LP, these results are consistent with the following hypotheses: apo E comprises an essential component of the site for normal recognition of remnants of triglyceride-rich lipoproteins by a specific hepatic receptor; accumulation of remnant lipoproteins in familial dys.beta.LP is caused by a lack of apo E-3 and E-4, which are the forms of this protein that are primarily recognized by the receptor; and the normal conversion of remnants of very low density lipoproteins to low density lipoproteins is mediated by the hepatic remnant receptor.

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