Disturbance of macrophage-associated lipid metabolism plays a key role in
atherosclerosis. Crosstalk between autophagy deficiency and
inflammation response in foam cells (FCs) through epigenetic regulation is still poorly understood. Here, we demonstrate that in macrophages,
oxidized low-density lipoprotein (
ox-LDL) leads to abnormal crosstalk between autophagy and
inflammation, thereby causing aberrant lipid metabolism mediated through a dysfunctional
transcription factor EB (TFEB)-P300-bromodomain-containing
protein 4 (BRD4) axis.
ox-LDL led to macrophage autophagy deficiency along with TFEB cytoplasmic accumulation and increased
reactive oxygen species generation. This activated P300 promoted BRD4 binding on the promoter regions of inflammatory genes, consequently contributing to
inflammation with
atherogenesis. Particularly,
ox-LDL activated BRD4-dependent super-enhancer associated with liquid-liquid phase separation (LLPS) on the regulatory regions of inflammatory genes.
Curcumin (Cur) prominently restored FCs autophagy by promoting TFEB nuclear translocation, optimizing
lipid catabolism, and reducing
inflammation. The consequences of P300 and BRD4 on super-enhancer formation and inflammatory response in FCs could be prevented by Cur. Furthermore, the anti-
atherogenesis effect of Cur was inhibited by macrophage-specific Brd4 overexpression or Tfeb knock-out in
Apoe knock-out mice via
bone marrow transplantation. The findings identify a novel TFEB-P300-BRD4 axis and establish a new epigenetic paradigm by which Cur regulates autophagy, inhibits
inflammation, and decreases
lipid content.