Document Detail

Internalization of modified lipids by CD36 and SR-A leads to hepatic inflammation and lysosomal cholesterol storage in Kupffer cells.
MedLine Citation:
PMID:  22470565     Owner:  NLM     Status:  MEDLINE    
BACKGROUND & AIMS: Non-alcoholic steatohepatitis (NASH) is characterized by steatosis and inflammation, which can further progress into fibrosis and cirrhosis. Recently, we demonstrated that combined deletion of the two main scavenger receptors, CD36 and macrophage scavenger receptor 1 (MSR1), which are important for modified cholesterol-rich lipoprotein uptake, reduced NASH. The individual contributions of these receptors to NASH and the intracellular mechanisms by which they contribute to inflammation have not been established. We hypothesize that CD36 and MSR1 contribute independently to the onset of inflammation in NASH, by affecting intracellular cholesterol distribution inside Kupffer cells (KCs).
METHODS & RESULTS: Ldlr(-/-) mice were transplanted with wild-type (Wt), Cd36(-/-) or Msr1(-/-) bone marrow and fed a Western diet for 3 months. Cd36(-/-)- and Msr1(-/-)- transplanted (tp) mice showed a similar reduction in hepatic inflammation compared to Wt-tp mice. While the total amount of cholesterol inside KCs was similar in all groups, KCs of Cd36(-/-)- and Msr1(-/-)-tp mice showed increased cytoplasmic cholesterol accumulation, while Wt-tp mice showed increased lysosomal cholesterol accumulation.
CONCLUSION: CD36 and MSR1 contribute similarly and independently to the progression of inflammation in NASH. One possible explanation for the inflammatory response related to expression of these receptors could be abnormal cholesterol trafficking in KCs. These data provide a new basis for prevention and treatment of NASH.
Veerle Bieghs; Fons Verheyen; Patrick J van Gorp; Tim Hendrikx; Kristiaan Wouters; Dieter Lütjohann; Marion J J Gijbels; Maria Febbraio; Christoph J Binder; Marten H Hofker; Ronit Shiri-Sverdlov
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't     Date:  2012-03-28
Journal Detail:
Title:  PloS one     Volume:  7     ISSN:  1932-6203     ISO Abbreviation:  PLoS ONE     Publication Date:  2012  
Date Detail:
Created Date:  2012-04-03     Completed Date:  2012-08-03     Revised Date:  2014-05-27    
Medline Journal Info:
Nlm Unique ID:  101285081     Medline TA:  PLoS One     Country:  United States    
Other Details:
Languages:  eng     Pagination:  e34378     Citation Subset:  IM    
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MeSH Terms
Antigens, CD36 / deficiency,  genetics,  metabolism*
Bone Marrow Transplantation
Cholesterol / metabolism*
Fatty Liver / metabolism,  pathology
Inflammation / pathology
Kupffer Cells / metabolism*,  pathology*
Lipid Metabolism*
Lipids / chemistry
Liver / metabolism,  pathology
Lysosomes / metabolism*
Mice, Knockout
Receptors, LDL / deficiency,  genetics,  metabolism
Scavenger Receptors, Class A / deficiency,  genetics,  metabolism*
Grant Support
F 3015-B19//Austrian Science Fund FWF
Reg. No./Substance:
0/Antigens, CD36; 0/Lipids; 0/Msr1 protein, mouse; 0/Receptors, LDL; 0/Scavenger Receptors, Class A; 97C5T2UQ7J/Cholesterol

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