Document Detail


Sterols and inhibitors of sterol transport modulate the degradation and secretion of macrophage ApoE: requirement for the C-terminal domain.
MedLine Citation:
PMID:  10760464     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
Macrophage-derived apoE, produced in the vessel wall, may have important effects during atherogenesis. The production of apoE by macrophages can be regulated at a transcriptional level by cellular differentiation state, cytokines and sterol loading. In addition, there are post-transcriptional and post-translational loci for regulation. We have recently identified an intermediate density cell membrane fraction in which the degradation of apoE can be modulated by sterols. Suppressing degradation of apoE in this fraction by pre-incubating cells in sterols led to enhanced apoE secretion. In this report we demonstrate that the suppressive effect of sterols on the degradation of newly synthesized apoE in this fraction depends on the presence on its C-terminal domain, by studying a macrophage cell line transfected to express a mutant form of apoE in which amino acids beyond amino acid 202 were deleted. In addition, two modulators of cellular sterol transport, progesterone and U1866A, inhibited the degradation of full-length apoE. In contrast, incubation of cells in the acyl-CoA:cholesterol acyltransferase inhibitor S58035 did not influence apoE degradation. As would be predicted based on the results of degradation assays, U1866A, but not S58035, increased the secretion of apoE from a cell line transfected to constitutively express full-length apoE cDNA. The effect of U1866A on apoE degradation, like the effect of sterol, required the presence of the apoE C-terminal domain. Our results indicate that alteration of intracellular sterol homeostasis by pre-incubation in sterols or by drugs that modify the subcellular transport of sterol, modulates the susceptibility of apoE to degradation and that this modulation requires the presence of C-terminal lipid binding domains.
Authors:
H Duan; D Gu; T Mazzone
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Publication Detail:
Type:  Journal Article; Research Support, U.S. Gov't, P.H.S.    
Journal Detail:
Title:  Biochimica et biophysica acta     Volume:  1484     ISSN:  0006-3002     ISO Abbreviation:  Biochim. Biophys. Acta     Publication Date:  2000 Apr 
Date Detail:
Created Date:  2000-06-23     Completed Date:  2000-06-23     Revised Date:  2007-11-14    
Medline Journal Info:
Nlm Unique ID:  0217513     Medline TA:  Biochim Biophys Acta     Country:  NETHERLANDS    
Other Details:
Languages:  eng     Pagination:  142-50     Citation Subset:  IM    
Affiliation:
Departments of Medicine and Biochemistry, Rush Medical College, Chicago, IL 60612, USA.
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MeSH Terms
Descriptor/Qualifier:
Apolipoproteins E / biosynthesis,  genetics,  metabolism*
Biological Transport / drug effects
Cell Line
Homeostasis
Hydroxycholesterols / pharmacology
Macrophages / drug effects*,  secretion
Mutation
Progesterone / pharmacology
Sterols / pharmacology*
Transfection
Grant Support
ID/Acronym/Agency:
HL 39653/HL/NHLBI NIH HHS
Chemical
Reg. No./Substance:
0/Apolipoproteins E; 0/Hydroxycholesterols; 0/Sterols; 2140-46-7/25-hydroxycholesterol; 57-83-0/Progesterone

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine


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