KNOCKOUT OF THE ABETALIPOPROTEINEMIA GENE IN MICE - REDUCED LIPOPROTEIN SECRETION IN HETEROZYGOTES AND EMBRYONIC LETHALITY IN HOMOZYGOTES

Abetalipoproteinemia, an inherited human disease characterized by a ne ar-complete absence of the apolipoprotein (apo) B-containing lipoprote ins in the plasma, is caused by mutations in the gene for microsomal t riglyceride transfer protein (MTP), We used gene targeting to knock ou t the mouse MTP gene (Mttp). In heterozygous knockout mice (Mttp +/-), the MTP mRNA, protein, and activity levels were reduced by 50%, in bo th liver and intestine. Compared with control mice (Mttp +/+), chow-fe d Mttp +/- mice had reduced plasma levels of low-density lipoprotein c holesterol and had a 28% reduction in plasma apoB100 levels. On a high -fat diet, the Mttp +/- mice exhibited a marked reduction in total pla sma cholesterol levels, compared with those in Mttp +/+ mice. Both the livers of adult Mttp +/- mice and the visceral endoderm of the yolk s acs 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 norma l levels of lipoprotein synthesis and secretion, and a complete defici ency of MTP causes lethal developmental abnormalities, perhaps because of an impaired capacity of the yolk sac to export lipids to the devel oping embryo.