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.
Keywords: ATG5, autophagy-related 5; Acetyl-H3, acetyl-histone 3; Atherosclerosis; Autophagy; BET, bromodomain and extra-terminal; BRD4; BRD4, bromodomain protein 4; CQ, chloroquine; CVDs, cardiovascular diseases; ChIP, chromatin immunoprecipitation; Cur, curcumin; Curcumin; Dil-ox-LDL, 1,1′-dioctadecyl-3,3,3′,3′-tetramethy-lindocarbocyanine perchlorate labeled oxidized low-density lipoprotein; FCs, foam cells; HFD, high-fat diet; IL-1β, interleukin 1β; Inflammation; LIR, LC3-interacting region; MCP-1, monocyte chemotactic protein 1; Macrophage; NAC, N-acetyl-l-cysteine; ORO, Oil red O; P300; ROS, reactive oxygen species; Re-ChIP, re-chromatin immunoprecipitation; SE, super-enhancer; TFEB; TFEB, transcription factor EB; TNF-α, tumor necrosis factor α; mTORC1, mammalian target of rapamycin complex 1; ox-LDL, oxidized low-density lipoprotein; qRT-PCR, quantitative real-time polymerase chain reaction; siRNAs, small interference RNAs.
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