The amino-terminal 1-185 domain of ApoE promotes the clearance of lipoprotein remnants in vivo. The carboxy-terminal domain is required for induction of hyperlipidemia in normal and ApoE-deficient mice

被引:22
作者
Kypreos, KE
Morani, P
van Dijk, KW
Havekes, LM
Zannis, VI
机构
[1] Boston Univ, Sch Med, Dept Med, Whitaker Cardiovasc Inst, Boston, MA 02118 USA
[2] Leiden Univ, Med Ctr, Dept Human & Clin Genet, Leiden, Netherlands
[3] TNO, IVVO, Gaubius Lab, NL-2300 AK Leiden, Netherlands
关键词
D O I
10.1021/bi002414a
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
Apolipoprotein E (apoE) promotes receptor-mediated catabolism of apoE-containing lipoprotein remnants. Impairments in remnant clearance are associated with type III hyperlipoproteinemia and premature atherosclerosis. In humans, apoE plasma levels correlate with plasma triglyceride levels, suggesting that excess apoE may also affect plasma triglyceride levels. We have used adenovirus-mediated gene transfer in mice to map the domains of apoE required for cholesterol and triglyceride clearance, in vivo. Adenovirus expressing apoE3 and apoE4 at doses of (1-2) x 10(9) pfu increased plasma cholesterol and triglyceride levels in normal C57BL6 mice and failed to normalize the high cholesterol levels of apoE-deficient mice due to induction of hypertriglyceridemia. In contrast, an adenovirus expressing the truncated apoE 1-185 form normalized the cholesterol levels of E-/- mice and did not cause hypertriglyceridemia. Northern blot analysis of hepatic RNA from mice expressing the full-length and the truncated apoE forms showed comparable steady-state apoE mRNA levels of the full-length apoE forms that cause hyperlipidemia and the truncated apoE forms that do not cause hyperlipidemia. The findings suggest that the amino-terminal residues 1-185 of apoE are sufficient for the clearance of apoE-containing lipoprotein remnants by the liver, whereas domains of the carboxy-terminal one-third of apoE are required for apoE-induced hyperlipidemia.
引用
收藏
页码:6027 / 6035
页数:9
相关论文
共 64 条
[1]   MECHANISM OF HYPERTRIGLYCERIDEMIA IN HUMAN APOLIPOPROTEIN-(APO)-CIII TRANSGENIC MICE - DIMINISHED VERY LOW-DENSITY-LIPOPROTEIN FRACTIONAL CATABOLIC RATE ASSOCIATED WITH INCREASED APO-CIII AND REDUCED APO-E ON THE PARTICLES [J].
AALTOSETALA, K ;
FISHER, EA ;
CHEN, XL ;
CHAJEKSHAUL, T ;
HAYEK, T ;
ZECHNER, R ;
WALSH, A ;
RAMAKRISHNAN, R ;
GINSBERG, HN ;
BRESLOW, JL .
JOURNAL OF CLINICAL INVESTIGATION, 1992, 90 (05) :1889-1900
[2]   Interaction of nascent ApoE2, ApoE3, and ApoE4 isoforms expressed in mammalian cells with amyloid peptide beta (1-40). Relevance to Alzheimer's disease [J].
Aleshkov, S ;
Abraham, CR ;
Zannis, VI .
BIOCHEMISTRY, 1997, 36 (34) :10571-10580
[3]   BINDING OF A HIGH REACTIVE HEPARIN TO HUMAN APOLIPOPROTEIN-E - IDENTIFICATION OF 2 HEPARIN-BINDING DOMAINS [J].
CARDIN, AD ;
HIROSE, N ;
BLANKENSHIP, DT ;
JACKSON, RL ;
HARMONY, JAK ;
SPARROW, DA ;
SPARROW, JT .
BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS, 1986, 134 (02) :783-789
[4]   IMPAIRED VERY LOW-DENSITY LIPOPROTEIN AND TRIGLYCERIDE REMOVAL IN BROAD BETA DISEASE - COMPARISON WITH ENDOGENOUS HYPERTRIGLYCERIDEMIA [J].
CHAIT, A ;
HAZZARD, WR ;
ALBERS, JJ ;
KUSHWAHA, RP ;
BRUNZELL, JD .
METABOLISM-CLINICAL AND EXPERIMENTAL, 1978, 27 (09) :1055-1066
[5]  
CLADARAS C, 1987, J BIOL CHEM, V262, P2310
[6]   Plasma concentration of apolipoprotein E in intermediate-sized remnant-like lipoproteins in normolipidemic and hyperlipidemic subjects [J].
Cohn, JS ;
Tremblay, M ;
Amiot, M ;
Bouthillier, D ;
Roy, M ;
Genest, J ;
Davignon, J .
ARTERIOSCLEROSIS THROMBOSIS AND VASCULAR BIOLOGY, 1996, 16 (01) :149-159
[7]   Phenotype-dependent differences in apolipoprotein E metabolism and in cholesterol homeostasis in human monocyte-derived macrophages [J].
Cullen, P ;
Cignarella, A ;
Brennhausen, B ;
Mohr, S ;
Assmann, G ;
von Eckardstein, A .
JOURNAL OF CLINICAL INVESTIGATION, 1998, 101 (08) :1670-1677
[8]   Novel mechanism for defective receptor binding of apolipoprotein E2 in type III hyperlipoproteinemia [J].
Dong, LM ;
Parkin, S ;
Trakhanov, SD ;
Rupp, B ;
Simmons, T ;
Arnold, KS ;
Newhouse, YM ;
Innerarity, TL ;
Weisgraber, KH .
NATURE STRUCTURAL BIOLOGY, 1996, 3 (08) :718-722
[9]  
DONG LM, 1994, J BIOL CHEM, V269, P22358
[10]   ROLE OF APOLIPOPROTEIN-E IN THE LIPOLYTIC CONVERSION OF BETA-VERY- LOW-DENSITY LIPOPROTEINS TO LOW-DENSITY LIPOPROTEINS IN TYPE-III HYPERLIPOPROTEINEMIA [J].
EHNHOLM, C ;
MAHLEY, RW ;
CHAPPELL, DA ;
WEISGRABER, KH ;
LUDWIG, E ;
WITZTUM, JL .
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA-BIOLOGICAL SCIENCES, 1984, 81 (17) :5566-5570