動脈粥樣硬化是由高血脂症所引起的一種發炎性疾病，也有證據顯示發炎和脂質代謝平衡是密切相關的。巨噬細胞除了調節免疫反應外，也能參與脂質代謝平衡，並在動脈粥樣硬化的進程中扮演關鍵性的角色。然而巨噬細胞是否參與在高血脂所誘導的發炎性疾病，像是動脈粥樣硬化當中，需要進一步的釐清與研究。過去幾年來，我們的研究團隊已成功證實轉錄因子CCAAT/enhancer-binding protein delta (CEBPD)在巨噬細胞發炎及癌症微環境中扮演重要角色。因此，本篇論文主要目的即剖析CEBPD是否參與調控巨噬細胞發炎與脂質代謝平衡，進而影響動脈粥樣硬化的進程。免疫螢光染色結果顯示在人類和小鼠動脈粥樣硬化斑塊中，CEBPD蛋白和巨噬細胞有共位現象，此外，骨髓移植實驗結果顯示接受Cebpd缺陷骨髓細胞的動脈粥樣硬化模式小鼠，在餵食高脂食物後也較不會有動脈粥樣硬化斑塊的形成。細胞實驗結果顯示p38MAPK/CREB這條訊息傳遞路徑能幫助脂質所誘導的CEBPD活化，並促進脂質堆積在M1巨噬細胞而不是在M2巨噬細胞。其調控機制包括PTX3所促進的脂質內吞作用增多及ABCA1所促進的脂質外排作用減少。我們也發現ZNF202能參與調控CEBPD所抑制的ABCA1基因轉錄作用。此外，我們也發現降血脂藥物simvastatin能透過p38MAPK/CREB這條訊息傳遞路徑來抑制CEBPD的活化，進而減少脂質在M1巨噬細胞的堆積。本篇論文強調發炎與脂質代謝平衡交互作用的重要性，並提供靶向巨噬細胞表型來治療心血管疾病的新見解。

Atherosclerosis is an inflammatory disease driven by hyperlipidemia. There are accumulating evidences to support that inflammation and lipid homeostasis are closely linked. Macrophages mediate innate immune responses and lipid homeostasis and act as a key player in atherosclerosis. However, the cross talk among these processes in the development and progression of atherosclerosis are not fully defined. For the past few years, our recent studies successfully demonstrated the important role of the transcription factor CCAAT/enhancer-binding protein delta (CEBPD) in inflammation and cancer microenvironment over macrophages. In this current study, we aimed to dissect whether CEBPD functions at the junction of inflammation and macrophage lipid homeostasis. We found that CEBPD colocalized with macrophages in human and mouse atherosclerotic plaques and that Cebpd deficiency in bone marrow cells suppressed atherosclerotic lesions in hyperlipidemic Apoe-/- mice. In response to modified LDL, the p38MAPK/CREB pathway contributed to CEBPD activation which promoted lipid accumulation in M1 macrophages but not in M2 macrophages. The underlying mechanisms involved in this process included an increase in pentraxin 3 (PTX3)-mediated macropinocytosis of LDL and a reduction in ATP-binding cassette subfamily A member 1 (ABCA1)-mediated cholesterol efflux. Also, we found that ZNF202 mediates CEBPD-repressed ABCA1 gene transcription. In addition, we found that simvastatin (a HMG-CoA reductase inhibitor) can target CEBPD to block lipid accumulation in M1 macrophages. In conclusion, this study underscores the importance of cross talk between inflammation and lipid homeostasis and provides new insight into targeting macrophage phenotypes and functions in cardiovascular diseases.

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