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

Abstract

The uptake and catabolism of lamellar complexes of rat 12MI4abeled apolipoprotein (apo) E with egg lecithin were increased severalfold in perfused livers of rats given large amounts of 17a-ethynylestradiol for 5 days. Estrogen-stimulated uptake of lamellar complexes of human apo E that contained al of the major normally occurring "isoforms" of the protein (apo E-1, E-2, E-3, and E4) was comparable to that of rat apo E. By contrast, uptake of complexes containing apo E from individuals with familial dysbetalipoproteinemia (dys#LP; characterized by a lack of apo E-3 and E4) was stimulated to a much smaller extent. With complexes containing individual isoforms of human apo E, it was shown that estrogen-stimulated hepatic uptake was largely confined to apo E-3 and E4; uptake of apo The metabolism of triglyceride-rich lipoproteins in the blood plasma of rats proceeds in two distinct steps (1). In the first, triglycerides in the core of the particles are removed in extrahepatic tissues by the action of lipoprotein lipase. In the second, the modified "remnant" lipoproteins are rapidly taken up by the liver or, at least in the case of hepatogenous very low density lipoproteins (VLDL), are converted in part to low density lipoproteins (LDL). During the first step, most of the apolipoproteins of small molecular weight (C apoproteins) are removed and transferred to high density lipoproteins (HDL). When the VLDL are converted to LDL, the arginine-rich apolipoprotein (apo E) is removed and the high molecular weight apolipoprotein (apo B) remains as the only protein component. Remnant lipoproteins containing apo E and apo B are rapidly taken up by the liver, whereas LDL that contain only apo B are removed very slowly from the blood, and it has been suggested that apo E is an important determinant of the hepatic uptake of remnant lipoproteins (2, 3). Uptake of chylomicron remnants by the perfused rat liver is saturable, consistent with a receptor-dependent process (4, 5). Indirect evidence suggests that the metabolism of triglyceride-rich lipoproteins in humans proceeds in the same two steps (1, 2, 6).In familial dysbetalipoproteinemia (dysfLP), a monogenic human disorder of lipoprotein metabolism, particles with the properties of remnants of chylomicrons and VLDL accumulate in the blood, and the concentration of LDL is reduced (2). Thus, when compared with their putative precursors, these particles are characterized by a higher ratio of cholesteryl esters to triglycerides in their core (7) and by an increased proportion of apo E on their surface (8). As shown by isoelectric focusing techniques (9, 10), apo E is normally composed of three or four major "isoforms" (apo E-1, E-2, E-3, and E-4). Apo E-4 is present in only about 25% of normal persons (variant trait). In familial dys(LP, apo E is grossly deficient or lacking in both apo E-3 and E-4, which raises the possibility that a structural abnormality of this protein impairs the hepatic uptake of remnants and their conversion to LDL.Recent research has shown that trea...

Determination by the SRID Method of Normal Values of Serum Apolipoproteins (A-I, A-II, B, C-II, C-III, and E) in Normolipidemic Healthy Japanese Subjects

“…In the present study, however, no difference was observed between the males and females subjects for apolipoprotein A-I. The apolipoprotein E level was higher in the females than in the males in all age groups above 10 years, and this result is in agreement with that reported by Havel et al [20] ; it seems of great significance that the results obtained by Havel et al could be confirmed in the present study for each of the age groups. Apolipoproteins A-I and A-II, B, and C-II and C-III are, respectively, the principal proteins of HDL, LDL, and TG-rich lipoprotein, and apolipoprotein E is thought to be deeply involved in the metabolism of cholesterol.…”

Diet-induced hyperlipoproteinemia and atherosclerosis in apolipoprotein E3-Leiden transgenic mice.

“…Every individual arterial lesion was classified accordingly. Within a group the total number of both mild lesions (categories [1][2][3] and moderate plus severe lesions (categories 4 and 5) of all mice was counted. After dividing the total number of lesions (mild and moderate plus severe, separately) by the number of mice per group, two separate mean scores for each group of animals were obtained.…”

“…Apolipoprotein E functions as a ligand for the receptor-mediated uptake of chylomicron and VLDL remnants by hepatic lipoprotein receptors (1)(2)(3). Normally, these remnant particles are rapidly removed from the circulation.…”

Apolipoprotein E polymorphism association with lipoprotein profile in endogenous hypertriglyceridemia and familial hypercholesterolemia.

“…Chylomicrons and large VLDL, whose clearance is regulated by apo E, have been postulated as possible effectors. The conjunction of a reduced cholesterol absorption in e2 subjects 34 - 35 and defective apo E2 remnant uptake 36 may decrease the delivery of cholesterol to the liver. This may result in the upregulation of liver LDL receptors and accelerated fractional catabolic rates of plasma LDL in apo E3/2 subjects.…”