Knockout of the abetalipoproteinemia gene in mice:: Reduced lipoprotein secretion in heterozygotes and embryonic lethality in homozygotes

被引:214
作者
Raabe, M
Flynn, LM
Zlot, CH
Wong, JS
Véniant, MM
Hamilton, RL
Young, SG
机构
[1] Gladstone Inst Cardiovasc Dis, San Francisco, CA 94141 USA
[2] Univ Calif San Francisco, Dept Med, San Francisco, CA 94143 USA
[3] Univ Calif San Francisco, Dept Anat, San Francisco, CA 94143 USA
关键词
D O I
10.1073/pnas.95.15.8686
中图分类号
O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];
学科分类号
07 ; 0710 ; 09 ;
摘要
Abetalipoproteinemia, an inherited human disease characterized by a near-complete absence of the apolipoprotein (apo) B-containing lipoproteins in the plasma, is caused by mutations in the gene for microsomal triglyceride transfer protein (MTP), We used gene targeting to knock out the mouse MTP gene (Mttp). In heterozygous knockout mice (Mttp +/-), the MTP mRNA, protein, and activity levels were reduced by 50%, in both liver and intestine. Compared with control mice (Mttp +/+), chow-fed Mttp +/- mice had reduced plasma levels of low-density lipoprotein cholesterol and had a 28% reduction in plasma apoB100 levels. On a high-fat diet, the Mttp +/- mice exhibited a marked reduction in total plasma cholesterol levels, compared with those in Mttp +/+ mice. Both the livers of adult Mttp +/- mice and the visceral endoderm of the yolk sacs from Mttp +/- embryos manifested an accumulation of cytosolic fat, All homozygous embryos (Mttp -/-) died during embryonic development. In the visceral endoderm of Mttp -/- yolk sacs, lipoprotein synthesis was virtually absent, and there was a marked accumulation of cytosolic fat droplets. In summary, half-normal MTP levels do not support normal levels of lipoprotein synthesis and secretion, and a complete deficiency of MTP causes lethal developmental abnormalities, perhaps because of an impaired capacity of the yolk sac to export lipids to the developing embryo.
引用
收藏
页码:8686 / 8691
页数:6
相关论文
共 41 条
[1]   Lipoproteins containing apolipoprotein B isolated from patients with abetalipoproteinemia and homozygous hypobetalipoproteinemia: Identification and characterization [J].
Aguie, GA ;
Rader, DJ ;
Clavey, V ;
Traber, MG ;
Torpier, G ;
Kayden, HJ ;
Fruchart, JC ;
Brewer, HB ;
Castro, G .
ATHEROSCLEROSIS, 1995, 118 (02) :183-191
[2]   Microsomal triacylglycerol transfer protein prevents presecretory degradation of apolipoprotein B-100 - A dithiothreitol-sensitive protease is involved [J].
Benoist, F ;
Nicodeme, E ;
GrandPerret, T .
EUROPEAN JOURNAL OF BIOCHEMISTRY, 1996, 240 (03) :713-720
[3]   INTESTINAL AND HEPATIC APOLIPOPROTEIN-B GENE-EXPRESSION IN ABETALIPOPROTEINEMIA [J].
BLACK, DD ;
HAY, RV ;
ROHWERNUTTER, PL ;
ELLINAS, H ;
STEPHENS, JK ;
SHERMAN, H ;
TENG, BB ;
WHITINGTON, PF ;
DAVIDSON, NO .
GASTROENTEROLOGY, 1991, 101 (02) :520-528
[4]  
BORCHARDT RA, 1987, J BIOL CHEM, V262, P16394
[5]   DEATH BEFORE BIRTH - CLUES FROM GENE KNOCKOUTS AND MUTATIONS [J].
COPP, AJ .
TRENDS IN GENETICS, 1995, 11 (03) :87-93
[6]  
Du EZ, 1996, J LIPID RES, V37, P1309
[7]  
Farese RV, 1996, J LIPID RES, V37, P347
[8]   KNOCKOUT OF THE MOUSE APOLIPOPROTEIN-B GENE RESULTS IN EMBRYONIC LETHALITY IN HOMOZYGOTES AND PROTECTION AGAINST DIET-INDUCED HYPERCHOLESTEROLEMIA IN HETEROZYGOTES [J].
FARESE, RV ;
RULAND, SL ;
FLYNN, LM ;
STOKOWSKI, RP ;
YOUNG, SG .
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 1995, 92 (05) :1774-1778
[9]   APOLIPOPROTEIN SYNTHESIS IN NORMAL AND ABETALIPOPROTEINEMIC INTESTINAL-MUCOSA [J].
GLICKMAN, RM ;
GLICKMAN, JN ;
MAGUN, A ;
BRIN, M .
GASTROENTEROLOGY, 1991, 101 (03) :749-755
[10]   MICROSOMAL TRIGLYCERIDE TRANSFER PROTEIN - A PROTEIN COMPLEX REQUIRED FOR THE ASSEMBLY OF LIPOPROTEIN PARTICLES [J].
GORDON, DA ;
WETTERAU, JR ;
GREGG, RC .
TRENDS IN CELL BIOLOGY, 1995, 5 (08) :317-321