Autor: |
Shaila Bhat, Manal Zabalawi, Mark C. Willingham, Gregory S. Shelness, Michael J. Thomas, Mary G. Sorci-Thomas |
Jazyk: |
angličtina |
Rok vydání: |
2004 |
Předmět: |
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Zdroj: |
Journal of Lipid Research, Vol 45, Iss 7, Pp 1207-1220 (2004) |
Druh dokumentu: |
article |
ISSN: |
0022-2275 |
DOI: |
10.1194/jlr.M300498-JLR200 |
Popis: |
From a total of 47 known apolipoprotein A-I (apoA-I) mutations, only 18 are linked to low plasma HDL apoA-I concentrations, and 78% of these map to apoA-I helices 6 and 7 (residues 143–186). Gene transfer and transgenic mouse studies have shown that several helix 6 apoA-I mutations have reduced hepatic HDL production. Our objective was to examine the impact of helix 6 modifications on intracellular biosynthetic processing and secretion of apoA-I. Cells were transfected with wild-type or mutant apoA-I, radiolabeled with [35S]Met/Cys, and then placed in unlabeled medium for up to 4 h. Results show that >90% of newly synthesized wild-type apoA-I was secreted by 60 min. Over the same length of time, only 20% of helix 6 deletion mutant (Δ6 apoA-I) was secreted, whereas 80% remained cell associated. Microscopic and biochemical studies revealed that cell-associated Δ6 apoA-I was located predominantly within the cytoplasm as lipid-protein inclusions, whereas wild-type apoA-I was localized in the endoplasmic reticulum/Golgi. Results using other helix deletions or helix 6 substitution mutations indicated that only complete removal of helix 6 resulted in massive cytoplasmic accumulation.These data suggest that alterations in native apoA-I conformation can lead to aberrant trafficking and accumulation of apolipoprotein-phospholipid structures. Thus, conformation-dependent alterations in intracellular trafficking and turnover may underlie the reduced plasma HDL concentrations observed in individuals harboring deletion mutations within helix 6. |
Databáze: |
Directory of Open Access Journals |
Externí odkaz: |
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