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Identifier 000374654
Title Ανάλυση του μονοπατιού βιογένεσης της HDL με μεταλλαξιογένεση της απολιποπρωτείνης Α-I
Alternative Title Analysis of the pathway of biogenesis of HDL by mutatios of apolipoprotein A-I
Author Κατεϊφίδης, Ανδρέας
Thesis advisor Καρδάσης, Δημήτριος
Reviewer Ζαννής, Βασίλειος
Ηλιόπουλος, Αριστείδης
Θερμού, Κυριακή
Παπαδάκη, Ελένη
Μπούμπας, Δημήτριος
Σουρβίνος, Γεώργιος
Abstract Apolipoprotein A-I is a key protein for the biogenesis of High Density Lipoproteins and protects from atherosclerosis. Mutations in apoA-I gene are associated with low HDL levels and predisposition to atherosclerosis. The purpose of the present thesis was to explore the structure-function relationship in human apoA-I and the role of specific amino acid residues in HDL biogenesis and maturation. The thesis is organized in two parts. Part I: Alteration of Negatively Charged Residues in the 89 to 99 Domain of ApoA-I Affects Lipid Homeostasis and the Maturation of HDL (J Lipid Res. 2011 Jul;52(7):1363-72). Adenovirus-mediated gene transfer in apoA-I-/- mice showed that an apoA-I[D89A/E91A/E92A] mutant increased plasma cholesterol and caused severe hypertriglyceridemia. HDL levels were reduced and approximately 40% of the apoA-I was distributed in VLDL/IDL. The HDL consisted of mostly spherical and few discoidal particles and contained preβ1 and α4-HDL subpopulations. The mutant protein had increased affinity for triglyceride-rich emulsions. The lipid, lipoprotein and HDL profiles of the apoA-I[K94A/K96A] mutant were similar, but not identical, to those of wild type apoA-I. Co-expression of apoA-I[D89A/E91A/E92A] and human lipoprotein lipase abolished hypertriglyceridemia, restored in part the α1,2,3,4 HDL subpopulations, redistributed apoA-I in the HDL2/HDL3 regions, but did not prevent the formation of discoidal HDL particles. We conclude that residues D89, E91 and E92 of apoA-I are important for plasma cholesterol and triglyceride homeostasis as well as for the maturation of HDL. The present and two previous studies raise the possibility that xvii mutations in apoA-I in the general population may alter the functions of apoA-I and HDL and contribute to hypertriglyceridemia. Part II: Contribution of the residues 218 to 226 of apoA-I in the biogenesis of HDL. Adenovirus mediated gene transfer of an apoA-I [L218A/L219A/V221A/L222A] mutant in apoA-I-/- mice resulted in decreased plasma cholesterol and apoA-I levels to approximately 10 % as compared to WT control and generated preβ and α4-HDL particles. The HDL cholesterol peak of the mutant protein was greatly diminished. When expressed in double deficient mice for apoA-I and apoE the apoAI[ L218A/L219A/V221A/L222A] mutant failed to form HDL particles as determined by 2D gel electrophoresis and electron microscopy. The apoA-I[E223A/K226A] mutant had similar plasma apoA-I levels and similar but not identical lipid and lipoprotein profiles with WT apoA-I. Overall the findings suggest that crucial changes in the C-terminal 218- 222 hydrophobic residues of apoA-I impair seriously the functional interactions of apoAI with ABCA1 and/or LCAT and inhibit biogenesis of HDL. In the context of this thesis we also investigated, in collaboration with other groups, the role of apoA-I C-terminus in endothelial transcytosis of HDL (J Biol Chem. 2011 Mar 11;286(10):7744-54), the bactericidal activity of apoA-I against Yersinia enterocolitica serotypre O:3 (manuscript in preparation) and apoA-I mutations in patients with increased risk of ischaemic heart disease and total mortality in the population of Copenhagen (J Intern Med. 2011 Mar 28. doi: 10.1111 in press)
Language Greek
Subject Apolipoprotein AI
Biochemistry
Gene transfer
HDL
Mutagenesis
Απολιποπρωτεϊνη Α-I
Μεταλλαξιογένεση
Ορθοκολικός καρκίνος
Issue date 2011
Collection   School/Department--School of Medicine--Department of Medicine--Doctoral theses
  Type of Work--Doctoral theses
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