BACKGROUND AND AIMS Fargesin mainly functions in the improvement of lipid metabolism and the inhibition of inflammation, but the role of fargesin in atherogenesis and the molecular mechanisms have not been defined. We aimed to explore if and how fargesin affects atherosclerosis by regulating lipid metabolism and inflammatory response. METHODS AND RESULTS ApoE-/- mice were fed a high-fat diet to form atherosclerotic plaques and then administrated with fargesin or saline via gavage. Oil Red O, HE and Masson staining were performed to assess atherosclerostic plaques in apoE-/- mice. [3H] labeled cholesterol was used to detect cholesterol efflux and reverse cholesterol transport (RCT) efficiency. Enzymatic methods were performed to analyze plasma lipid profile in apoE-/- mice. Immunohistochemistry was used to analyze macrophage infiltration. THP-1-derived macrophages were incubated with fargesin or not. Both Western blot and qRT-PCR were applied to detect target gene expression. Oil Red O staining was applied to examine lipid accumulation in THP-1-derived macrophages. ELISA and qRT-PCR were used to examine the levels of inflammatory mediotors. We found that fargesin reduced atherosclerotic lesions by elevating efficiency of RCT and decreasing inflammatory response via upregulation of ABCA1 and ABCG1 expression in apoE-/- mice. Further, fargesin reduced lipid accumulation in THP-1-derived macrophages. Besides, fargesin increased phosphorylation of CEBPα in Ser21 and then upregulated LXRα, ABCA1 and ABCG1 expression in THP-1-derived macrophages. In addition, fargesin could reduce ox-LDL-induced inflammatory response by inactivation of the TLR4/NF-κB pathway. CONCLUSION These results suggest that fargesin inhibits atherosclerosis by promoting RCT process and reducing inflammatory response via CEBPαS21/LXRα and TLR4/NF-κB pathways, respectively.

中文翻译：

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Fargesin通过促进胆固醇逆向转运和减少炎症反应来减轻动脉粥样硬化。

背景与目的Fargesin主要在脂质代谢改善和炎症抑制中起作用，但尚未确定fargesin在动脉粥样硬化中的作用及其分子机制。我们旨在探讨fargesin是否以及如何通过调节脂质代谢和炎症反应影响动脉粥样硬化。方法和结果给ApoE-/-小鼠喂食高脂饮食以形成动脉粥样硬化斑块，然后通过管饲法将其加入Fargesin或生理盐水。进行油红O，HE和Masson染色以评估apoE-/-小鼠的动脉粥样斑块。[3H]标记的胆固醇用于检测胆固醇外流和逆转胆固醇转运（RCT）效率。进行酶促方法以分析apoE-/-小鼠的血浆脂质谱。免疫组织化学用于分析巨噬细胞浸润。THP-1衍生的巨噬细胞是否与Fargesin一起孵育。Western blot和qRT-PCR均用于检测靶基因表达。油红O染色用于检查THP-1来源的巨噬细胞中脂质的积累。ELISA和qRT-PCR用于检查炎症介导水平。我们发现，fargesin通过提高RCT的效率和通过上调apoE-/-小鼠中ABCA1和ABCG1表达的炎症反应来减少动脉粥样硬化病变。此外，fargesin减少了THP-1衍生的巨噬细胞中脂质的积累。此外，fargesin增加了Ser21中CEBPα的磷酸化，然后上调了THP-1来源的巨噬细胞中LXRα，ABCA1和ABCG1的表达。此外，fargesin可以通过使TLR4 /NF-κB通路失活来减少ox-LDL诱导的炎症反应。