Lengths of truncated forms of apolipoprotein B (apoB) determine their intestinal production.
Most truncations of apoB associated with hypobetalipoproteinemia (HBL) result from frame shift mutations of the apoB gene that give rise to premature stop codons and truncations of C-terminal sequences. The "natural" truncation, apoB-48, arises from a stop codon by cotranscriptional editing of intestinal apoB-100 mRNA. We hypothesized that mutant apoB mRNA would be normally edited and that only those apoB truncations shorter than apoB-48 would be expressed in enterocytes, because translation of mRNAs giving rise to longer truncations would be interrupted by the apoB-48 stop codon. Duodenal mucosal biopsies from HBL and normolipidemic subjects were incubated with [35S]methionine, apoB was immunoprecipitated and bands were visualized by autoradiography. Biopsies of three subjects heterozygous for apoB-54.8 or apoB-89 synthesized virtually only apoB-48. By contrast, the biopsy of a subject heterozygous for apoB-40 synthesized both apoB-48 and apoB-40. Thus, enterocytes in HBL edit the mutant mRNAs similarly to the apoB mRNA of normal enterocytes and the small intestine of heterozygotes with truncations longer than apoB-48 produce only apoB-48, as the apoB-48 stop codon terminates translation proximal to the mutant stop codon. By contrast, intestines of heterozygotes with truncations shorter than apoB-48 produce the truncated apoB because the mutant stop codon stops translation before the apoB-48 stop codon. In conclusion, only the liver secretes apoB truncations larger than apoB-48, whereas shorter truncations are secreted by both liver and intestine.
Krul
E S
ES
Department of Internal Medicine, Washington University School of Medicine, St. Louis, MO 63110.
Tang
J
J
Kettler
T S
TS
Clouse
R E
RE
Schonfeld
G
G
D001055:Apolipoproteins B / Q000096:biosynthesis* / Q000097:blood / Q000235:genetics*; D002784:Cholesterol / Q000097:blood; D008078:Cholesterol, LDL / Q000097:blood; D003062:Codon; D004386:Duodenum; D005260:Female; D016368:Frameshift Mutation; D006579:Heterozygote; D006801:Humans; D006995:Hypobetalipoproteinemias / Q000097:blood / Q000235:genetics* / Q000378:metabolism*; D007413:Intestinal Mucosa / Q000378:metabolism*; D008297:Male; D008715:Methionine / Q000378:metabolism; D010641:Phenotype; D012323:RNA Processing, Post-Transcriptional; D012333:RNA, Messenger / Q000378:metabolism*; D012016:Reference Values; D013462:Sulfur Radioisotopes; D014280:Triglycerides / Q000097:blood
D001055:Apolipoproteins B; D008078:Cholesterol, LDL; D003062:Codon; D012333:RNA, Messenger; D013462:Sulfur Radioisotopes; D014280:Triglycerides; D002784:Cholesterol; D008715:Methionine