title: Lengths of truncated forms of apolipoprotein B (apoB) determine their intestinal production.
abstract: 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.
authors: Department of Internal Medicine, Washington University School of Medicine, St. Louis, MO 63110.
authors: E S
authors: ES
authors: Krul
authors: J
authors: J
authors: Tang
authors: T S
authors: TS
authors: Kettler
authors: R E
authors: RE
authors: Clouse
authors: G
authors: G
authors: Schonfeld
mesh_terms: 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
chemical_list: D001055:Apolipoproteins B; D008078:Cholesterol, LDL; D003062:Codon; D012333:RNA, Messenger; D013462:Sulfur Radioisotopes; D014280:Triglycerides; D002784:Cholesterol; D008715:Methionine