心脏脂毒性（CL）的致病基础是甘油三酯（TG）等脂毒性物质堆积，而心肌细胞过度摄取脂肪酸是其最重要原因。脂蛋白脂肪酶（LPL）是影响脂肪酸摄取的关键酶。过氧化物酶体增殖物激活受体-β（PPAR-β）已被证实可在心肌细胞内抑制LPL且对CL有益。近年针对不同细胞研究均显示白细胞介素-33（IL-33）可减少细胞内TG含量；此外又发现IL-33可上调肝脏PPAR-β。我们前期实验发现IL-33减少心肌细胞内脂质含量，同时上调PPAR-β及抑制LPL。IL-33调控PPAR-β及LPL并改善CL机制不清。本项目拟利用本单位已有自发出现过度摄取脂肪酸和CL的转基因小鼠，通过实验观察IL-33对CL的作用及其对心肌细胞表达PPAR-β和LPL的影响；通过上调或下调PPAR-β及LPL表达，探讨它们是否参与介导IL-33抗CL过程；最后通过双荧光素酶报告基因、定点突变、EMSA及CHIP等方法阐明IL-33调控PPAR-β的具体机制，为临床防治CL提供更多思路。

Fatty acids (FAs) are the main source of energy and the lipids origin for heart. Although they are of major importance to heart, excessive uptake of FAs causes lipid overload or cardiac lipotoxicity (CL) and may compromise cardiac function, possibly leading to cardiomyopathy. Accumulations of triglyceride (TG) and other lipids and metabolites are the pathological basis of CL. Most of the FAs taken by heart are derived from lipoprotein lipase (LPL) dependent hydrolysis of circulating triglyceride-rich lipoproteins. It has been demonstrated that excessive LPL plays a part in CL. Peroxisome Proliferator-activated receptor-β (PPAR-β) has been shown to inhibit LPL and ameliorate CL in vivo. Recently, IL-33 has been found to reduce TG accumulation in both macrophages and white adipose cultures. Besides, it is shown to up-regulate PPAR-β in liver. Our preliminary study showed a beneficial effect of IL-33 in reducing TG in cardiomyocyte cell line, accompanied with increased PPAR-β mRNA level and decreased LPL. The associations among IL-33, PPAR-β, LPL and CL are unknown. We proposed a novel mechanism that IL-33 up-regulated PPAR-β, which in turn inhibited LPL and lowered FAs uptake and finally ameliorated CL. To demonstrate these, we used our α-MHC-PPARγ transgenic mice, which occur excessive FAs uptake and severe CL in adulthood. By in vivo study, we would explore the effects of IL-33 on CL and on the expression profiles of PPAR-β and LPL. With the help of self-complementary double strain adeno-associated virus serotype 9 (dsAAV9), we are going to up-regulate or down-regulate PPAR-β and LPL, both in vivo and in vitro, demonstrating the roles of PPAR-β and LPL played in the process of IL-33-mediating anti-CL. After elucidating the roles of PPAR-β and LPL in the beneficial effects of IL-33 on CL, our next aim is to investigate the precise mechanism of IL-33 regulating PPAR-β in cardiomyocytes. Since the transcriptional factor, CCAAT/enhancer binding protein-alpha (C/EBP-α), which is down-regulated by IL-33, has been shown to inhibit transcriptional activity of PPAR-β promoter in keratinocytes, we sought to use dsAAV9 again to increase or decrease C/EBP-α expression, exploring their effects on PPAR-β expressions and demonstrating the role of C/EBP-α in the regulatory processing of IL-33 on PPAR-β. After a determination of the transcriptional mechanism of IL-33 on PPAR-β by using the actinomycin-D, we would explore the precise mechanism that C/EBP-α acts on PPAR-β promoter using dual-luciferase reporter gene analysis, EMSA and CHIP. Our works would help to elucidate the effects of IL-33 on CL and its underline mechanism, which may help to prevention and treat CL in clinical practice.