动脉粥样硬化是心血管疾病的主要病理之一，增强胆固醇逆转运利于减缓动脉粥样硬化的发展。前期结果表明：山楂叶总黄酮改善血脂、诱导参与胆固醇逆转运关键基因ABCA1、ABCG1、SR-BI的表达，减少巨噬细胞胆固醇的沉积；文献报道山楂叶总黄酮诱导动脉粥样硬化大鼠动脉壁ABCA1表达，据此推断：山楂叶总黄酮促进胆固醇逆转运进而具有抑制动脉粥样硬化发展的作用。为证实该假说，拟以山楂叶总黄酮喂食apoE基因敲除小鼠，检测血脂、胆固醇沉积、代谢、动脉斑块形成等药效学指标来评价山楂叶总黄酮对apoE敲除小鼠的影响。随后，从胆固醇逆转运这一影响动脉粥样硬化发展的关键生理学过程入手，以山楂叶总黄酮、含药血清以及高含量的牡荆素-鼠李糖苷和金丝桃苷研究其影响动脉粥样硬化发展的生物学机制：考察影响胆固醇逆转运的关键基因的表达调控及信号通路，胆固醇摄取、流出，进而初步阐明山楂叶总黄酮影响动脉粥样硬化发展的生物学机制。

Atherosclerosis is the main pathological basis of cardiovascular disease while it could be improved by enhancing reverse cholesterol transport(RCT). It is reported that ABCA1 expression in artery wall could be induced by Hawthorn Leaves Flavonoids(HLF). We previously demonstrated that the expression of macrophage ABCA1, ABCG1 and SR-BI can be induced by HLF at indicated concentration. Based on this observation, we presume that Hawthorn Leaves Flavonoids promote the RCT, thus HLF inhibit the development of Atherosclerosis. In order to test and verify this hypothesis, we planed to examine cholesterol efflux and uptake by macrophages and liver cells respectively by method employing HLF and radiolabled cholesterol administrated to cells and apoE knockout mice. Hopely, we would verify compound(s) promote RCT in vivo. To further disclose the mechanism of HLF effect on RCT, we planed to examine the gene expression of ABCA1, ABCG1 and SR-BI which considered to play important role in enhancing RCT. We aimed at finding out the effective compound of HLF promoting RCT and the mechnism beneath. This is a benefit attempt to study the way of HLF to play efficacy.

背景：山楂叶及山楂叶总黄酮是常见的用于降低血液中脂含量的药材及药物。山楂叶总黄酮是山楂叶提取物的主要成份。其降脂作用机制并不明确。本项研究旨在从胆固醇代谢角度去探讨山楂叶总黄酮降低血脂的生物学机制。主要研究内容：（1）山楂叶总黄酮对apoE-/-小鼠血脂的影响；（2）山楂叶总黄酮影响apoE-/-小鼠血脂的生物学机制；（3）利用生物信息学方法研究动脉粥样硬化发展中关键基因及信号通路。重要结果和关键数据：（1）山楂叶总黄酮喂食apoE-/-小鼠后，主动脉斑块附着显著减少；（2）山楂叶总黄酮喂食apoE-/-小鼠后，总胆固醇及低密度脂蛋白胆固醇水平显著下降，而甘油三脂、高密度脂蛋白胆固醇水平保持不变；（3）山楂叶总黄酮PPARa表达上调，SREBP1-c表达下调；山楂叶总黄酮喂食apoE-/-小鼠会上调肝脏LDLR表达。取肝脏组织，检测低密度脂蛋白上调，显示山楂叶总黄酮促进肝脏LDLR表达，进而提示：山楂叶总黄酮促进肝脏对胆固醇代谢；(5)山楂叶总黄酮会促进胆固醇外流并抑制泡沫细胞生成；（6）山楂叶总黄酮促进小鼠体内胆固醇代谢；（7）生物信息学方法分析动脉粥样硬化发展中的关键基因及信号通路，结果表明，信号通路主要富集在NFkB、细胞因子相互作用、趋化因子及TNF信号等通路。科学意义：通过本项研究，初步阐明山楂叶总黄酮减缓动脉粥样硬化发展的生物学机制，并且通过对动脉粥样硬化发展中关键基因及信号通路的分析，为后续深入研究其作用机制奠定了基础。本项研究，也为心脑血管药理研究方法提供一种借鉴。