ROS via BTK-p300-STAT1-PPARγ signaling activation mediates cholesterol crystals-induced CD36 expression and foam cell formation.

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.