title: Dual mechanisms for the low plasma levels of truncated apolipoprotein B proteins in familial hypobetalipoproteinemia. Analysis of a new mouse model with a nonsense mutation in the Apob gene.
abstract: Familial hypobetalipoproteinemia (FHbeta), a syndrome characterized by low plasma cholesterol levels, is caused by mutations in the apo-B gene that interfere with the synthesis of apo-B100. FHbeta mutations frequently lead to the synthesis of a truncated form of apo-B, which typically is present in plasma at < 5% of the levels of apo-B100. Although many FHbeta mutations have been characterized, the basic mechanisms causing the low plasma levels of truncated apo-B variants have not been defined. We used gene targeting to create a mutant allele that exclusively yields a truncated apo-B, apo-B83. In mice heterozygous for the Apob83 allele, plasma levels and the size and density distribution of apo-B83-containing lipoproteins were strikingly similar to those observed in humans with FHbeta and an apo-B83 mutation. Analysis of mice carrying the Apob83 mutation revealed two mechanisms for the low plasma levels of apo-B83. First, Apob83 mRNA levels and apo-B83 secretion were reduced 76 and 72%, respectively. Second, apo-B83 was removed rapidly from the plasma, compared with apo-B100. This mouse model provides a new level of understanding of FHbeta and adds new insights into apo-B metabolism.
authors.affiliation: Gladstone Institute of Cardiovascular Disease, University of California, San Francisco, California 94141-9100, USA.
authors.forename: E
authors.initials: E
authors.lastname: Kim
authors.forename: C M
authors.initials: CM
authors.lastname: Cham
authors.forename: M M
authors.initials: MM
authors.lastname: Véniant
authors.forename: P
authors.initials: P
authors.lastname: Ambroziak
authors.forename: S G
authors.initials: SG
authors.lastname: Young
mesh_terms: D000483:Alleles; D000818:Animals; D053299:Apolipoprotein B-100; D001055:Apolipoproteins B / Q000096:biosynthesis* / Q000235:genetics* / Q000378:metabolism; D001057:Apolipoproteins E / Q000502:physiology; D002784:Cholesterol / Q000097:blood; D003001:Cloning, Molecular; D018076:DNA, Complementary / Q000235:genetics; D006995:Hypobetalipoproteinemias / Q000235:genetics* / Q000378:metabolism*; D007413:Intestinal Mucosa / Q000378:metabolism; D008075:Lipoproteins, HDL / Q000032:analysis / Q000097:blood / Q000378:metabolism; D008077:Lipoproteins, LDL / Q000032:analysis / Q000097:blood / Q000378:metabolism; D008079:Lipoproteins, VLDL / Q000032:analysis / Q000097:blood / Q000378:metabolism; D008099:Liver / Q000166:cytology / Q000378:metabolism; D051379:Mice; D008817:Mice, Mutant Strains / Q000002:abnormalities; D016297:Mutagenesis, Site-Directed; D010375:Pedigree; D016133:Polymerase Chain Reaction; D012333:RNA, Messenger / Q000032:analysis / Q000378:metabolism; D011973:Receptors, LDL / Q000502:physiology; D014158:Transcription, Genetic
chemical_list: D053299:Apolipoprotein B-100; D001055:Apolipoproteins B; D001057:Apolipoproteins E; D018076:DNA, Complementary; D008075:Lipoproteins, HDL; D008077:Lipoproteins, LDL; D008079:Lipoproteins, VLDL; D012333:RNA, Messenger; D011973:Receptors, LDL; D002784:Cholesterol