TR4 nuclear receptor functions as a fatty acid sensor to modulate CD36 expression and foam cell formation.
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.
Xie
Shaozhen
S
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
YF
Kim
Eungseok
E
Chen
Lu-Min
LM
Ni
Jing
J
Fang
Lei-Ya
LY
Liu
Su
S
Lin
Shin-Jen
SJ
Abe
Jun-Ichi
J
Berk
Bradford
B
Ho
Feng-Ming
FM
Chang
Chawnshang
C
D000818:Animals; D001483:Base Sequence; D018955:CD36 Antigens / Q000235:genetics / Q000378:metabolism*; D002467:Cell Nucleus / Q000187:drug effects / Q000378:metabolism*; D005231:Fatty Acids, Unsaturated / Q000378:metabolism*; D005487:Foam Cells / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism*; D008024:Ligands; D051379:Mice; D008969:Molecular Sequence Data; D011485:Protein Binding / Q000187:drug effects; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D011987:Receptors, Steroid / Q000378:metabolism*; D011988:Receptors, Thyroid Hormone / Q000378:metabolism*; D020218:Response Elements / Q000235:genetics; D000077154:Rosiglitazone; D045162:Thiazolidinediones / Q000494:pharmacology; D014158:Transcription, Genetic / Q000187:drug effects; D015533:Transcriptional Activation / Q000187:drug effects / Q000235:genetics
D018955:CD36 Antigens; D005231:Fatty Acids, Unsaturated; D008024:Ligands; C490514:Nr2c2 protein, mouse; D012333:RNA, Messenger; D011987:Receptors, Steroid; D011988:Receptors, Thyroid Hormone; D045162:Thiazolidinediones; D000077154:Rosiglitazone