我们前期在动脉粥样硬化(As)小鼠中证实，病理条件下高密度脂蛋白(HDL)表现为抗As 的“失功能”。值得关注的是，这种氧化炎性的HDL下调巨噬细胞清道夫受体BI (SR-BI)表达的同时，能诱发细胞自噬标志LC3 II/I增高，而控制溶酶体生成的转录因子TFEB表达下调，使胞内脂质积聚于溶酶体；进一步发现体内高表达抗氧化酶或多肽可重塑“失功能”HDL的抗氧化能力，并与巨噬细胞自噬和脂质水平的调节相关。鉴于HDL功能均涉及细胞受体依赖的信号途径，而SR-BI可介导正常及氧化HDL的脂质转运，本课题拟关注一条溶酶体依赖的脂质降解途径——脂噬，从细胞受体信号与脂噬通路的联系——这一新角度，探讨天然及“失功能”HDL对巨噬细胞产生的信号差异及机制，并尝试用高表达TFEB手段改善脂噬溶酶体通路的顺应性，探讨其对巨噬细胞脂质流动及As斑块的调节，此将有助于揭示相关心血管疾病的新分子机制及药物靶点。

Our previous studies with atherosclerosis mouse models have shown that the HDL particles are dysfunctional under various pathological conditions. The dysfunctional HDL is characterized by increased oxidation and pro-inflammatory properties. It is noteworthy that the dysfunctional HDL could down-regulate the expression of scavenger receptor BI (SR-BI), induce an increase in autophagic markers LC3 II/I ratio, while suppress the expression of transcription factor EB (TFEB), a master gene for lysosomal biogenesis, contributing to lipid accumulation in lysosomes of macrophages. Furthermore, we found that overexpression of antioxidase PON1, methionine sulfoxide reductase A (MsrA), or an HDL-binding apoE-derived peptide EpK could restore the anti-oxidative capacity of the dysfunctional HDL, and revealed that the autophagy activity is correlated with the lipid homeostasis in macrophages. Since HDL functions are carried out through direct interacting with its receptors localized on the cell surface followed by generation of intracellular signals, and SR-BI is a specific HDL receptor which recognizes both native and dysfunctional HDL and mediates cholesterol transport by a dual-flux feature, we aim to explore the relationship between receptor-mediated cellular signaling pathways and lipophagy, an autophagy selectively involved in lipid degradation. We propose to examine the role of SR-BI in mediating different signaling pathways by native and dysfunctional HDLs in macrophages and determine the underlying mechanisms. We will also test if lipophagy lysosomal pathway is improved by overexpression of TFEB in bone marrow-derived macrophages, and examine the impact on lipid transport in macrophages and atherosclerotic lesion formation in mice. The proposed studies will elucidate new molecular mechanisms for atherogenesis and suggest new drug targets for Atherosclerosis-related cardiovascular diseases.