Pathway of biogenesis of apolipoprotein E-containing HDL in vivo with the participation of ABCA1 and LCAT.
We have investigated the ability of apoE (apolipoprotein E) to participate in the biogenesis of HDL (high-density lipoprotein) particles in vivo using adenovirus-mediated gene transfer in apoA-I-/- (apolipoprotein A-I) or ABCA1-/- (ATP-binding cassette A1) mice. Infection of apoA-I-/- mice with 2x10(9) pfu (plaque-forming units) of an apoE4-expressing adenovirus increased both HDL and the triacylglycerol-rich VLDL (very-low-density lipoprotein)/IDL (intermediate-density lipoprotein)/LDL (low-density lipoprotein) fraction and generated discoidal HDL particles. ABCA1-/- mice treated similarly failed to form HDL particles, suggesting that ABCA1 is essential for the generation of apoE-containing HDL. Combined infection of apoA-I-/- mice with a mixture of adenoviruses expressing both apoE4 (2x10(9) pfu) and human LCAT (lecithin:cholesterol acyltransferase) (5x10(8) pfu) cleared the triacylglycerol-rich lipoproteins, increased HDL and converted the discoidal HDL into spherical HDL. Similarly, co-infection of apoE-/- mice with apoE4 and human LCAT corrected the hypercholesterolaemia and generated spherical particles, suggesting that LCAT is essential for the maturation of apoE-containing HDL. Overall, the findings indicate that apoE has a dual functionality. In addition to its documented functions in the clearance of triacylglycerol-rich lipoproteins, it participates in the biogenesis of HDL-sized apoE-containing particles. HDL particles generated by this pathway may account at least for some of the atheroprotective functions of apoE.
Kypreos
Kyriakos E
KE
Molecular Genetics, Whitaker Cardiovascular Institute, Departments of Medicine and Biochemistry, Boston University School of Medicine, 715 Albany Street W509, Boston, MA 02118, USA.
Zannis
Vassilis I
VI
D064286:ATP Binding Cassette Transporter 1; D018528:ATP-Binding Cassette Transporters / Q000235:genetics / Q000378:metabolism*; D000256:Adenoviridae / Q000235:genetics; D000409:Alanine / Q000235:genetics / Q000378:metabolism; D000818:Animals; D016632:Apolipoprotein A-I / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D001057:Apolipoproteins E / Q000096:biosynthesis* / Q000097:blood; D006801:Humans; D057927:Hydrophobic and Hydrophilic Interactions; D008075:Lipoproteins, HDL / Q000096:biosynthesis* / Q000097:blood; D053858:Metabolic Networks and Pathways; D051379:Mice; D018345:Mice, Knockout; D007862:Phosphatidylcholine-Sterol O-Acyltransferase / Q000235:genetics / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics; D011994:Recombinant Proteins / Q000235:genetics / Q000378:metabolism
C577836:ABCA1 protein, human; D064286:ATP Binding Cassette Transporter 1; D018528:ATP-Binding Cassette Transporters; D016632:Apolipoprotein A-I; D001057:Apolipoproteins E; D008075:Lipoproteins, HDL; D012333:RNA, Messenger; D011994:Recombinant Proteins; C025121:apolipoprotein E-rich HDL; D007862:Phosphatidylcholine-Sterol O-Acyltransferase; D000409:Alanine