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A more recent version of this article appeared on July 1, 2004

Papers In Press, published online ahead of print April 1, 2004
J. Lipid Res., doi:10.1194/jlr.M300498-JLR200
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Submitted on December 3, 2003
Revised on March 25, 2004
Accepted on March 26, 2004

Quality control in the ApoA-I secretory pathway: Deletion of ApoA-I helix 6 leads to the formation of cytosolic phospholipid inclusions

Shaila Bhat, Manal Zabalawi, Mark C. Willingham, Gregory S. Shelness, Michael J. Thomas, and Mary G. Sorci-Thomas

Pathology, Wake Forest University Health Sciences, Winston-Salem, NC 27157

Corresponding Author: msthomas{at}wfubmc.edu

From a total of 47 known 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, then placed in unlabeled medium for up to 4 hr. 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 (6 apoA-I) was secreted, while 80% remained cell-associated. Microscopic and biochemical studies revealed that cell-associated 6 apoA-I was located predominately within the cytoplasm as lipid-protein inclusions while wild-type apoA-I was localized in the ER/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 apoprotein-phospholipid structures. Thus, conformation dependent alterations in intracellular trafficking and turnover may underlie reduced plasma HDL concentrations observed in individuals harboring deletion mutations within helix 6.


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J. S. Owen, M. S. Bharadwaj, M. J. Thomas, S. Bhat, M. P. Samuel, and M. G. Sorci-Thomas
Ratio determination of plasma wild-type and L159R apoA-I using mass spectrometry: tools for studying apoA-IFin
J. Lipid Res., January 1, 2007; 48(1): 226 - 234.
[Abstract] [Full Text] [PDF]


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