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Calpain-mediated cleavage negatively regulates the expression level of ABCG1.
MedLine Citation:
PMID:  21295304     Owner:  NLM     Status:  Publisher    
Abstract/OtherAbstract:
OBJECTIVE: The ATP-binding cassette transporter ABCG1 mediates cholesterol efflux from macrophages, and prevents the progression of macrophage foam-cell formation. Much less is known about the regulatory mechanism of ABCG1, although its physiological importance is becoming clearer. Here, we show the role of calpain in ABCG1 degradation. METHODS AND RESULTS: Purified μ-calpain cleaved ABCG1 in crude membrane fractions prepared from human ABCG1-expressing HEK293 (ABCG1-HEK) cells. In ABCG1-HEK cells, calpeptin treatment, a calpain inhibitor, inhibited ABCG1 degradation, and thereby increased the expression and cholesterol efflux function of ABCG1. Biotinylation study demonstrated greater ABCG1 induction with calpeptin treatment in cell surface than that in whole cell lysates. Together with the result that increased ABCG1 expression with calpeptin treatment was observed under clathrin heavy-chain (CHC) knockdown conditions, where ABCG1 internalization was prevented, calpain is considered to catalyze ABCG1 cleavage on the plasma membrane. In mouse peritoneal macrophages as well as in ABCG1-HEK cells, calpeptin treatment inhibited ABCG1 degradation and enhanced ABCG1 expression, even under CHC-depleted conditions. CONCLUSION: These observations indicate that calpain promotes ABCG1 degradation by cleaving cell surface-resident ABCG1, and consequently reduces the expression and cholesterol efflux function of ABCG1. Inhibition of ABCG1 cleavage by calpain could be a novel approach to suppress the progression of atherosclerosis.
Authors:
Natsuki Hori; Hisamitsu Hayashi; Yuichi Sugiyama
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Publication Detail:
Type:  JOURNAL ARTICLE     Date:  2011-1-19
Journal Detail:
Title:  Atherosclerosis     Volume:  -     ISSN:  1879-1484     ISO Abbreviation:  -     Publication Date:  2011 Jan 
Date Detail:
Created Date:  2011-2-7     Completed Date:  -     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  0242543     Medline TA:  Atherosclerosis     Country:  -    
Other Details:
Languages:  ENG     Pagination:  -     Citation Subset:  -    
Copyright Information:
Copyright © 2011 Elsevier Ireland Ltd. All rights reserved.
Affiliation:
Laboratory of Molecular Pharmacokinetics, Graduate School of Pharmaceutical Sciences, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan.
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