Probing the pathways of chylomicron and HDL metabolism using adenovirus-mediated gene transfer.
OBJECTIVE
This review clarifies the functions of key proteins of the chylomicron and the HDL pathways.


RESULTS
Adenovirus-mediated gene transfer of several apolipoprotein (apo)E forms in mice showed that the amino-terminal 1-185 domain of apoE can direct receptor-mediated lipoprotein clearance in vivo. Clearance is mediated mainly by the LDL receptor. The carboxyl-terminal 261-299 domain of apoE induces hypertriglyceridemia, because of increased VLDL secretion, diminished lipolysis and inefficient VLDL clearance. Truncated apoE forms, including apoE2-202, have a dominant effect in remnant clearance and may have future therapeutic applications for the correction of remnant removal disorders. Permanent expression of apoE and apoA-I following adenoviral gene transfer protected mice from atherosclerosis. Functional assays, protein cross-linking, and adenovirus-mediated gene transfer of apoA-I mutants in apoA-I deficient mice showed that residues 220-231, as well as the central helices of apoA-I, participate in ATP-binding cassette transporter A1-mediated lipid efflux and HDL biogenesis. Following apoA-I gene transfer, an amino-terminal deletion mutant formed spherical alpha-HDL, a double amino- and carboxyl-terminal deletion mutant formed discoidal HDL, and a carboxyl-terminal deletion mutant formed only pre-beta-HDL. The findings support a model of cholesterol efflux that requires direct physical interactions between apoA-I and ATP-binding cassette transporter A1, and can explain Tangier disease and other HDL deficiencies.


CONCLUSIONS
New insights are provided into the role of apoE in cholesterol and triglyceride homeostasis, and of apoA-I in the biogenesis of HDL. Clearance of the lipoprotein remnants and increase in HDL synthesis are obvious targets for therapeutic interventions.
Zannis
Vassilis I
VI
Molecular Genetics, Boston University School of Medicine, Boston, Massachusetts 02118-2394, USA. vzannis!bu.edu
Chroni
Angeliki
A
Kypreos
Kyriakos E
KE
Kan
Horng-Yuan
HY
Cesar
Thais Borges
TB
Zanni
Eleni E
EE
Kardassis
Dimitris
D
D064286:ATP Binding Cassette Transporter 1; D018528:ATP-Binding Cassette Transporters / Q000235:genetics / Q000378:metabolism; D000256:Adenoviridae / Q000235:genetics*; D000818:Animals; D016632:Apolipoprotein A-I / Q000235:genetics* / Q000378:metabolism; D001057:Apolipoproteins E / Q000235:genetics* / Q000378:metabolism; D001161:Arteriosclerosis / Q000235:genetics / Q000378:metabolism; D002914:Chylomicrons / Q000378:metabolism*; D005822:Genetic Vectors; D006801:Humans; D006952:Hyperlipoproteinemia Type III / Q000235:genetics / Q000378:metabolism; D008075:Lipoproteins, HDL / Q000378:metabolism*; D051379:Mice; D023421:Models, Animal; D015398:Signal Transduction; D013631:Tangier Disease / Q000235:genetics / Q000378:metabolism
D064286:ATP Binding Cassette Transporter 1; D018528:ATP-Binding Cassette Transporters; D016632:Apolipoprotein A-I; D001057:Apolipoproteins E; D002914:Chylomicrons; D008075:Lipoproteins, HDL