TRANSLOCATION OF APOLIPOPROTEIN-B ACROSS THE ENDOPLASMIC-RETICULUM ISBLOCKED IN ABETALIPOPROTEINEMIA

Abetalipoproteinemia (ABL) is an autosomal recessive disease character ized by the inability of the liver and intestine to secrete apolipopro tein B (apoB). Mutations in the microsomal triglyceride transfer prote in (MTP) gene, bur not the apoB gene, are responsible for the ABL phen otype. It is not clear how loss of MTP in ABL patients leads to a comp lete, but specific, block in the secretion of apoB. It is to this ques tion that our work is directed. In cultured cells lacking MTP, translo cation of apoB is completely arrested, leading to the hypothesis that apoB requires MTP in order to completely enter the lumen of the endopl asmic reticulum, the site of lipoprotein assembly. We examined this hy pothesis by determining the presence in plasma of distinct N-terminal apoB peptides, produced exclusively from translocation arrested apoB, in the plasma of six ABL patients and six normal subjects. The data sh ow that N-terminal apoB peptides are present in the plasma of six ABL patients, whereas intact apoB-100 was barely detectable. Moreover, the plasma of all six ABL patients displayed a 2000-fold increase in the amount of an 85 kDa N-terminal apoB peptide relative to apoB-100. Thes e data provide the first in vivo data supporting the essential role th at MTP plays in apoB translocation. In normal humans, varied expressio n of MTP may be responsible for the post-transcriptional regulation of apoB secretion.