Severe hypercholesterolemia, impaired fat tolerance, and advanced atherosclerosis in mice lacking both low density lipoprotein receptor-related protein 5 and apolipoprotein E

被引:108
作者
Magoori, K
Kang, MJ
Ito, MR
Kakuuchi, H
Ioka, RX
Kamataki, A
Kim, DH
Asaba, H
Iwasaki, S
Takei, YA
Sasaki, M
Usui, S
Okazaki, M
Takahashi, S
Ono, M
Nose, M
Sakai, J
Fujino, T
Yamamoto, TT
机构
[1] Tohoku Univ, Ctr Gene Res, Aoba Ku, Sendai, Miyagi 9818555, Japan
[2] Chonnam Natl Univ, Dept Anim Sci, Coll Agr, Kwangju 500600, South Korea
[3] Ehime Univ, Sch Med, Dept Pathol, Ehime 7910295, Japan
[4] Tokyo Med & Dent Univ, Chem Lab, Coll Liberal Arts & Sci, Chiba 2820827, Japan
[5] Osaka City Univ, Dept Food & Human Hlth Sci, Grad Sch Human Life Sci, Osaka 5588585, Japan
[6] Tohoku Univ, Grad Sch Med, Div Nephrol Endocrinol & Vasc Med, Dept Med, Sendai, Miyagi 9808574, Japan
[7] Japan Sci & Technol Corp, ERATO, Yanagisawa Orphan Receptor Project, Tokyo 1350064, Japan
[8] Fukui Med Univ, Dept Internal Med 3, Fukui 9101193, Japan
关键词
D O I
10.1074/jbc.M211987200
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
LDL receptor-related protein 5 (LRP5) plays multiple roles, including embryonic development and bone accrual development. Recently, we demonstrated that LRP5 is also required for normal cholesterol metabolism and glucose-induced insulin secretion. To further define the role of LRP5 in the lipoprotein metabolism, we compared plasma lipoproteins in mice lacking LRP5, apolipoprotein E (apoE), or both (apoE;LRP5 double knockout). On a normal chow diet, the apoE;LRP5 double knockout mice (older than 4 months of age) had similar to60% higher plasma cholesterol levels compared with the age-matched apoE knockout mice. In contrast, LRP5 deficiency alone had no significant effects on the plasma cholesterol levels. High performance liquid chromatography analysis of plasma lipoproteins revealed that cholesterol levels in the very low density lipoprotein and low density lipoprotein fractions were markedly increased in the apoE;LRP5 double knockout mice. There were no apparent differences in the pattern of apoproteins between the apoE knockout mice and the apoE; LRP5 double knockout mice. The plasma clearance of intragastrically loaded triglyceride was markedly impaired by LRP5 deficiency. The atherosclerotic lesions of the apoE;LRP5 double knockout mice aged 6 months were similar to3-fold greater than those in the age-matched apoE-knockout mice. Furthermore, histological examination revealed highly advanced arthrosclerosis, with remarkable accumulation of foam cells and destruction of the internal elastic lamina in the apoE;LRP5 double knockout mice. These data suggest that LRP5 mediates both apoE-dependent and apoE-independent catabolism of plasma lipoproteins.
引用
收藏
页码:11331 / 11336
页数:6
相关论文
共 28 条
[11]   A new low density lipoprotein receptor belated protein, LRP5, is expressed in hepatocytes and adrenal cortex, and recognizes apolipoprotein E [J].
Kim, DH ;
Inagaki, Y ;
Suzuki, T ;
Ioka, RX ;
Yoshioka, SZ ;
Magoori, K ;
Kang, MJ ;
Cho, Y ;
Nakano, AZ ;
Liu, Q ;
Fujino, T ;
Suzuki, H ;
Sasano, H ;
Yamamoto, TT .
JOURNAL OF BIOCHEMISTRY, 1998, 124 (06) :1072-1076
[12]   A mutation in the LDL receptor-related protein 5 gene results in the autosomal dominant high-bone-mass trait [J].
Little, RD ;
Carulli, JP ;
Del Mastro, RG ;
Dupuis, J ;
Osborne, M ;
Folz, C ;
Manning, SP ;
Swain, PM ;
Zhao, SC ;
Eustace, B ;
Lappe, MM ;
Spitzer, L ;
Zweier, S ;
Braunschweiger, K ;
Benchekroun, Y ;
Hu, XT ;
Adair, R ;
Chee, L ;
FitzGerald, MG ;
Tulig, C ;
Caruso, A ;
Tzellas, N ;
Bawa, A ;
Franklin, B ;
McGuire, S ;
Nogues, X ;
Gong, G ;
Allen, KM ;
Anisowicz, A ;
Morales, AJ ;
Lomedico, PT ;
Recker, SM ;
Van Eerdewegh, P ;
Recker, RR ;
Johnson, ML .
AMERICAN JOURNAL OF HUMAN GENETICS, 2002, 70 (01) :11-19
[13]   GENETIC-DEFECTS IN LIPOPROTEIN METABOLISM - ELEVATION OF ATHEROGENIC LIPOPROTEINS CAUSED BY IMPAIRED CATABOLISM [J].
MAHLEY, RW ;
WEISGRABER, KH ;
INNERARITY, TL ;
RALL, SC .
JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION, 1991, 265 (01) :78-83
[14]   LDL-receptor-related protein 6 is a receptor for Dickkopf proteins [J].
Mao, BY ;
Wu, W ;
Li, Y ;
Hoppe, D ;
Stannek, P ;
Glinka, A ;
Niehrs, C .
NATURE, 2001, 411 (6835) :321-325
[15]   Low-density lipoprotein receptor-related protein-5 binds to Axin and regulates the canonical Wnt signaling pathway [J].
Mao, JH ;
Wang, JY ;
Liu, B ;
Pan, WJ ;
Farr, GH ;
Flynn, C ;
Yuan, HD ;
Takada, S ;
Kimelman, D ;
Li, L ;
Wu, DQ .
MOLECULAR CELL, 2001, 7 (04) :801-809
[16]   WNT GENES [J].
NUSSE, R ;
VARMUS, HE .
CELL, 1992, 69 (07) :1073-1087
[17]  
Okazaki M, 2000, HDB LIPOPROTEIN TEST, P647
[18]   GENERATION OF MICE CARRYING A MUTANT APOLIPOPROTEIN-E GENE INACTIVATED BY GENE TARGETING IN EMBRYONIC STEM-CELLS [J].
PIEDRAHITA, JA ;
ZHANG, SH ;
HAGAMAN, JR ;
OLIVER, PM ;
MAEDA, N .
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 1992, 89 (10) :4471-4475
[19]   An LDL-receptor-related protein mediates Wnt signalling in mice [J].
Pinson, KI ;
Brennan, J ;
Monkley, S ;
Avery, BJ ;
Skarnes, WC .
NATURE, 2000, 407 (6803) :535-538
[20]   Inhibition of adipogenesis by Wnt signaling [J].
Ross, SE ;
Hemati, N ;
Longo, KA ;
Bennett, CN ;
Lucas, PC ;
Erickson, RL ;
MacDougald, OA .
SCIENCE, 2000, 289 (5481) :950-953