title: ROS via BTK-p300-STAT1-PPARγ signaling activation mediates cholesterol crystals-induced CD36 expression and foam cell formation.
abstract: In understanding the mechanisms of cholesterol in the pathogenesis of atherosclerosis, previous studies from other laboratories have demonstrated that cholesterol crystals (CC) induce scavenger receptor CD36 expression and NLRP3-mediated inflammasome formation. In elucidating the mechanisms by which CC could enhance CD36 expression and foam cell formation, here we report that CC via NADPH and xanthine oxidases-mediated ROS production activates BTK, a non-receptor tyrosine kinase. In addition, CC induce p300 tyrosine phosphorylation and activation in a BTK-dependent manner, which in turn, leads to STAT1 acetylation and its interaction with PPARγ in CD36 expression, oxLDL uptake and foam cell formation. Furthermore, p300, STAT1 and PPARγ bound to a STAT binding site at -107 nt in CD36 promoter and enhanced its activity in ROS and BTK-dependent manner. Disruption of this STAT binding site by site-directed mutagenesis abolished CC-induced CD36 promoter activity. Together these results reveal for the first time that CC via producing ROS and activating BTK causes p300-mediated STAT1 acetylation and its interaction with PPARγ in CD36 expression, oxLDL uptake and foam cell formation.
authors.affiliation: Department of Physiology, University of Tennessee Health Science Center, Memphis, TN 38163, USA.
authors.forename: Sivareddy
authors.initials: S
authors.lastname: Kotla
authors.affiliation: Department of Physiology, University of Tennessee Health Science Center, Memphis, TN 38163, USA.
authors.forename: Nikhlesh K
authors.initials: NK
authors.lastname: Singh
authors.affiliation: Department of Physiology, University of Tennessee Health Science Center, Memphis, TN 38163, USA. Electronic address: rgadipar@uthsc.edu.
authors.forename: Gadiparthi N
authors.initials: GN
authors.lastname: Rao
mesh_terms: D000107:Acetylation; D000077329:Agammaglobulinaemia Tyrosine Kinase; D000818:Animals; D018955:CD36 Antigens / Q000235:genetics / Q000378:metabolism*; D002454:Cell Differentiation; D049109:Cell Proliferation; D002784:Cholesterol / Q000494:pharmacology*; D003460:Crystallization; D005487:Foam Cells / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D005786:Gene Expression Regulation; D006801:Humans; D008077:Lipoproteins, LDL / Q000235:genetics / Q000378:metabolism; D017737:Macrophages, Peritoneal / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D051379:Mice; D009249:NADP / Q000378:metabolism; D047495:PPAR gamma / Q000235:genetics / Q000378:metabolism*; D061251:Primary Cell Culture; D011505:Protein-Tyrosine Kinases / Q000235:genetics / Q000378:metabolism*; D017382:Reactive Oxygen Species / Q000378:metabolism*; D050794:STAT1 Transcription Factor / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D000074084:THP-1 Cells; D050880:p300-CBP Transcription Factors / Q000235:genetics / Q000378:metabolism*; D000099224:p300-CBP-Associated Factor
chemical_list: D000077329:Agammaglobulinaemia Tyrosine Kinase; D018955:CD36 Antigens; D002784:Cholesterol; D008077:Lipoproteins, LDL; D009249:NADP; D047495:PPAR gamma; D011505:Protein-Tyrosine Kinases; D017382:Reactive Oxygen Species; D050794:STAT1 Transcription Factor; D050880:p300-CBP Transcription Factors; D000099224:p300-CBP-Associated Factor; C494079:STAT1 protein, human; C099252:oxidized low density lipoprotein; C000625949:BTK protein, human