APO-B GENE KNOCKOUT IN MICE RESULTS IN EMBRYONIC LETHALITY IN HOMOZYGOTES AND NEURAL-TUBE DEFECTS, MALE-INFERTILITY, AND REDUCED HDL CHOLESTEROL ESTER AND APO-A-I TRANSPORT RATES IN HETEROZYGOTES

apo B is a structural constituent of several classes of lipoprotein pa rticles, including chylomicrons, VLDL, and LDL, To better understand t he role of apo B in the body, we have used gene targeting in embryonic stem cells to create a null apo B allele in the mouse, Homozygous apo B deficiency led to embryonic lethality, with resorption of all embry os by gestational day 9, Heterozygotes showed an increased tendency to intrauterine death with some fetuses having incomplete neural tube cl osure and some live-born heterozygotes developing hydrocephalus. The m ajority of male heterozygotes were sterile, although the genitourinary system and sperm were grossly normal, Viable heterozygotes had normal triglycerides, but total, LDL, and HDL cholesterol levels were decrea sed by 37, 37, and 39%, respectively, Hepatic and intestinal apo B mRN A levels were decreased in heterozygotes, presumably contributing to t he decreased LDL levels through decreased synthesis of apo B-containin g lipoproteins, Kinetic studies indicated that heterozygotes had decre ased transport rates of HDL cholesterol ester and apo A-I. As liver an d intestinal apo A-I mRNA levels were unchanged, the mechanism for dec reased apo A-I transport must be posttranscriptional, Heterozygotes al so had normal cholesterol absorption and a normal response of tbe plas ma lipoprotein pattern to chronic consumption of a high fat, high chol esterol, Western-type diet. In summary, we report a mouse model for ap o B deficiency with several phenotypic features that were unexpected b ased on clinical studies of apo B-deficient humans, such as embryonic lethality in homozygotes and neural tube closure defects, male inferti lity, and a major defect in HDL production in heterozygotes, This mode l presents an opportunity to study the mechanisms underlying these phe notypic changes.