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PMID: 19666541 Published · ppublish English Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't

TR4 nuclear receptor functions as a fatty acid sensor to modulate CD36 expression and foam cell formation.

Proceedings of the National Academy of Sciences of the United States of America ·Vol. 106 ·No. 32 ·2009-08-11 ·Pages 13353-8

Xie S, Lee YF, Kim E, Chen LM, Ni J, Fang LY, Liu S, Lin SJ, Abe J, Berk B, Ho FM, Chang C

Abstract

Testicular orphan nuclear receptor 4 (TR4) is an orphan member of the nuclear receptor superfamily with diverse physiological functions. Using TR4 knockout (TR4(-/-)) mice to study its function in cardiovascular diseases, we found reduced cluster of differentiation (CD)36 expression with reduced foam cell formation in TR4(-/-) mice. Mechanistic dissection suggests that TR4 induces CD36 protein and mRNA expression via a transcriptional regulation. Interestingly, we found this TR4-mediated CD36 transactivation can be further enhanced by polyunsaturated fatty acids (PUFAs), such as omega-3 and -6 fatty acids, and their metabolites such as 15-hydroxyeico-satetraonic acid (15-HETE) and 13-hydroxy octa-deca dieonic acid (13-HODE) and thiazolidinedione (TZD)-rosiglitazone. Both electrophoretic mobility shift assays (EMSA) and chromatin immunoprecipitation (ChIP) assays demonstrate that TR4 binds to the TR4 response element located on the CD36 5'-promoter region for the induction of CD36 expression. Stably transfected TR4-siRNA or functional TR4 cDNA in the RAW264.7 macrophage cells resulted in either decreased or increased CD36 expression with decreased or increased foam cell formation. Restoring functional CD36 cDNA in the TR4 knockdown macrophage cells reversed the decreased foam cell formation. Together, these results reveal an important signaling pathway controlling CD36-mediated foam cell formation/cardiovascular diseases, and findings that TR4 transactivation can be activated via its ligands/activators, such as PUFA metabolites and TZD, may provide a platform to screen new drug(s) to battle the metabolism syndrome, diabetes, and cardiovascular diseases.

MeSH Terms
Animals Base Sequence CD36 Antigens/genetics,metabolism Cell Nucleus/drug effects,metabolism Fatty Acids, Unsaturated/metabolism Foam Cells/cytology,drug effects,metabolism Ligands Mice Molecular Sequence Data Protein Binding/drug effects RNA, Messenger/genetics,metabolism Receptors, Steroid/metabolism Receptors, Thyroid Hormone/metabolism Response Elements/genetics Rosiglitazone Thiazolidinediones/pharmacology Transcription, Genetic/drug effects Transcriptional Activation/drug effects,genetics
Chemicals
CD36 Antigens Fatty Acids, Unsaturated Ligands Nr2c2 protein, mouse RNA, Messenger Receptors, Steroid Receptors, Thyroid Hormone Thiazolidinediones Rosiglitazone
Authors & Affiliations
12 authors, click to expand affiliations / ORCID
Xie Shaozhen
George Whipple Lab for Cancer Research, Department of Pathology, and Cardiovascular Research Institute, University of Rochester Medical Center, Rochester, NY 14642, USA.
Lee Yi-Fen
Kim Eungseok
Chen Lu-Min
Ni Jing
Fang Lei-Ya
Liu Su
Lin Shin-Jen
Abe Jun-Ichi
Berk Bradford
Ho Feng-Ming
Chang Chawnshang
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Article Info
Journal
Proceedings of the National Academy of Sciences of the United States of America
Abbr.
Proc Natl Acad Sci U S A
ISSN
1091-6490
DOI
10.1073/pnas.0905724106
Published
2009-08-11
Epub
2009-00-28
Pages
13353-8
Language
English
Region
United States
NLM ID
7505876
PMCID
PMC2726407
Subset
IM
Grants
NIDDK NIH HHS · R01 DK073414 · United States
NIDDK NIH HHS · DK073414 · United States
External Links
PubMed source DOI: 10.1073/pnas.0905724106 PMC Full Text View journal details
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