Apolipoprotein E3-Leiden. A new variant of human apolipoprotein E associated with familial type III hyperlipoproteinemia

Apolipoprotein (apo) E is a 34.2 kDa glycoprotein synthesized by the liver and to a lesser extent by peripheral tissues ( 1 ). It is associated in plasma with triglyceride-rich lipoproteins (TRL) and HDL particles ( 2 ). ApoE plays a central role in mediating hepatic recognition and uptake of TRL and their remnants by acting as a ligand for lipoprotein binding to the LDL receptor, LDL receptorrelated protein, and glycosaminoglycans ( 3 ). ApoE may also activate enzymes involved in lipoprotein metabolism, including hepatic lipases, cholesteryl ester transfer protein, and lecithin cholesteryl:acytransferase ( 4 ). The apoE gene is polymorphic, with three common alleles coding for three major isoforms identifi ed as E2, E3, and E4 ( 5 ).Type III hyperlipidemia, also known as dysbetalipoproteinemia, is a rare form of genetic dyslipidemia characterized by elevated plasma cholesterol and triglycerides and the presence of cholesterol-enriched remnant particles, collectively known as ␤ -VLDL ( 6 ). The accumulation of ␤ -VLDL particles may be associated with impaired TRL catabolism ( 7 ). Type III hyperlipidemic subjects may have severe xanthomatosis and signifi cantly increased risk of developing premature atherosclerosis ( 8 ). The majority of type III hyperlipidemic subjects are homozygotes for the apoE2 allele of the apoE ( APOE ) gene. However, <10% of apoE2 homozygotes develop hyperlipidemia, and most apoE2/E2 subjects are either normolipidemic or hypocholesterolemic ( 6 ). The onset of hyperlipidemia may be associated with additional genetic factors and/or environmental factors such as obesity, diabetes, and menopausal status ( 6 ). The regulation of lipoprotein transport in subjects with the apoE2/E2 genotype, in particular those withAbstract The effect of apolipoprotein (apo) E genotype on apoB-100 metabolism was examined in three normolipidemic apoE2/E2, fi ve type III hyperlipidemic apoE2/E2, and fi ve hyperlipidemic apoE3/E2 subjects using simultaneous administration of 131 I-VLDL and 125 I-LDL, and multicompartmental modeling. Compared with normolipidemic apoE2/E2 subjects, type III hyperlipidemic E2/E2 subjects had increased plasma and VLDL cholesterol, plasma and VLDL triglycerides, and VLDL and intermediate density lipoprotein (IDL) apoB concentrations ( P < 0.05). These abnormalities were chiefl y a consequence of decreased VLDL and IDL apoB fractional catabolic rate (FCR). Compared with hyperlipidemic E3/E2 subjects, type III hyperlipidemic E2/E2 subjects had increased IDL apoB concentration and decreased conversion of IDL to LDL particles ( P < 0.05). In a pooled analysis, VLDL cholesterol was positively associated with VLDL and IDL apoB concentrations and the proportion of VLDL apoB in the slowly turning over VLDL pool, and was negatively associated with VLDL apoB FCR after adjusting for subject group. VLDL triglyceride was positively associated with VLDL apoB concentration and VLDL and IDL apoB production rates after adjusting for subject group. A defective apoE contributes to altered lipoprotein me...

Section: Discussionmentioning

confidence: 99%

Effect of apolipoprotein E genotype on apolipoprotein B-100 metabolism in normolipidemic and hyperlipidemic subjects

Ooi

Janus

Grant

et al. 2010

“…Development of these animal models started with the discovery of human mutations in individuals with lipoprotein disorders. The best-known examples include mutations in the LDL receptor (LDLr) in association with familial hypercholesterolemia (FH) and mutations in ApoE (including ApoE Leiden) in cases of Type III hyperlipoproteinemia (HLP) (3)(4)(5). As a result, LDLr -/-, Apo E -/-, and ApoE3-Leiden transgenic mice have been widely used as mouse models of atherosclerosis (6)(7)(8)(9).…”

Section: Cell Culture Studiesmentioning

confidence: 99%

siRNA-induced liver ApoB knockdown lowers serum LDL-cholesterol in a mouse model with human-like serum lipids

Tadin‐Strapps¹,

Peterson

Cumiskey

et al. 2011

This article is available online at http://www.jlr.org Coronary atherosclerosis is the most prevalent disease in industrialized societies. Although numerous advances have been made in understanding the underlying causes of atherosclerosis and treatment thereof, this condition still remains the leading cause of death in the Western world. The most important risk factor for atherosclerosis is hyperlipidemia ( 1 ). Development of atherosclerosis correlates with high levels of low density lipoprotein cholesterol (LDL). As a result, several therapies have been developed for management of LDL levels. Among these, statins are most widely used ( 2 ). However, there is a range of statin response in humans, and a subset of familial hyperlipidemia patients is unresponsive to statins, prompting the development of additional therapies.

“…ApoE2 (Arg158 → Cys) and apoE3-Leiden cause similarly severe hyperlipidemia in humans (5,7,8), while only apoE2 causes severe hyperlipidemia in mice (20,27,28). We investigated the effect of human apoE variants on the removal of remnant lipoproteins using intact livers.…”

mentioning

confidence: 99%

Chylomicron remnant uptake in the livers of mice expressing human apolipoproteins E3, E2 (Arg158→Cys), and E3-Leiden

Lee

Grosskopf

Choi

et al. 2004

Apolipoprotein E2 (apoE2) and apoE3-Leiden cause chylomicron remnant accumulation (type III hyperlipidemia). However, the degree of dyslipidemia and its penetrance are different in humans and mice. Remnant uptake by isolated liver from apoE ؊ / ؊ mice transgenic for human apoE2, apoE3-Leiden, or apoE3 was measured. In the presence of both LDL receptor (LDLR) and LDL receptor-related protein (LRP), remnant uptake was apoE3 Ͼ E3-Leiden Ͼ E2 mice. Absence of LDLR reduced uptake in apoE3 and apoE3-Leiden-secreting livers but not in apoE2-secreting livers. LRP inhibition with receptor-associated protein reduced uptake in apoE3-and apoE2-secreting livers, but not in apoE3-Leiden-secreting livers, regardless of the presence of LDLR. Fluorescently labeled remnants clustered with LRP in apoE3-secreting livers only in the absence of LDLR, but clustered in livers that expressed apoE2 even in the presence of LDLR, and did not cluster with LRP in livers of apoE3-Leiden even in the absence of LDLR. Remnants were reconstituted with the three human apoE isoforms. Removal by liver of mApoe ؊ / ؊ / mldlr ؊ / ؊ mice expressing the human LDLR was slightly greater than removal in the previous experiments with apoE3 Ͼ E2 Ͼ E3-Leiden. Thus, in vivo, human apoE2 is cleared primarily by LRP, apoE3-Leiden is cleared only by the LDLR, and apoE3 is cleared by both. -Lee, S-J., I. Grosskopf, S. Y. Choi, and A. D. Cooper. Chylomicron remnant uptake in the livers of mice expressing human apoE3, apoE2 (Arg158 → Cys), and apoE3-Leiden.