Cathepsin L与AMPK信号通路互作调控脂质沉积的分子机理研究

Cathepsin L is an important lysosomal protein, which contributes to many physiologic process. The level and activity of Cathepsin L are also strongly correlated with obesity and other metabolic diseases. Recent studies demonstrate that Cathepsin L play important role in the above pathobiology by degrading extracellular matrix (ECM). Cathepsin L may also participate in regulation of intracellular signal related with obesity and other metabolic diseases. However, the molecular mechanism is still unclear. Quite similar with mammalian, the genome of C. elegans, an emerging model for studying the basic biology of obesity, contains most of the genes related with fat deposition, which is crucial for the occurrence and development of obesity.　We found that CPL-1, the homologous of Cathepsin L in C. elegans, may interact with AMPK signal pathway, participating in regulation of fat deposition. Thus, the research contents of this program are as follows. First, to clarify the interaction of Cathepsin L and fat deposition. Second, to investigate the crosstalk between Cathepsin L and AMPK in the regulation of fat deposition. Third, to analysis whether this mechanism is conserved in mouse. The research of this program will provide a deepen understanding of the molecular mechanism of Cathepsin L interacting with intracellular signal in regulation of fat deposition. In addition, the program will also enrich the current theory of Cathepsins regulation of obesity occurrence and development, and provide theoretical basis for targeting Cathepsins to prevent and treat obesity and related metabolic diseases.

组织蛋白酶L是重要的溶酶体蛋白，影响体内众多生理过程。机体中组织蛋白酶L的水平及活性与肥胖和其他代谢疾病密切相关。现有研究表明，组织蛋白酶L可能通过降解细胞外基质参与上述病理过程。组织蛋白酶L还有可能通过细胞内信号调控了脂质沉积，但具体分子机理尚不清楚。与哺乳动物类似，模式生物秀丽线虫基因组中存在大部分参与脂质沉积的基因。我们目前的研究发现：组织蛋白酶L参与了线虫脂质沉积，而且可能通过AMPK信号发挥调控功能。在此基础上，我们提出：1）明确组织蛋白酶L与脂质沉积的关系；2）组织蛋白酶L与AMPK信号通路在调控脂质沉积中的机制；3）组织蛋白酶L通过AMPK信号调控脂质沉积机制在小鼠中的保守性分析。本项目将加深我们对组织蛋白酶L通过细胞内信号调控脂质沉积的分子机理的理解，丰富组织蛋白酶调控肥胖发生发展的现有理论；同时很可能为通过干预组织蛋白酶来防治肥胖及相关代谢疾病提供新靶点和途径。

作为营养感知和脂肪降解的中心细胞器，溶酶体对于细胞内部脂质代谢至关重要。然而，溶酶体及其内部的水解酶是否参与了营养诱导的脂质沉积目前还不清楚。本项目的研究结果表明，外周组织的溶酶体蛋白酶Cathepsin L 通过抑制中枢神经系统中serotonin的合成调控了营养诱导的脂质沉积。在线虫中抑制溶酶体的功能可以有效减少高糖饮食诱导的脂肪沉积。敲除或者通过RNAi降低cpl-1的表达，可以阻止高糖饮食诱导的溶酶体激活，从而减少脂肪沉积。进一步的机制研究表明，外周组织的cpl-1可以调控中枢神经组织中serotonin的表达，进而通过AMPK调控脂肪酸β氧化。最后，我们利用基因敲除小鼠证明小鼠中存在类似的保守调控机制。本研究发现了溶酶体在营养感知和脂肪沉积中新的调控机制，为开发以组织蛋白酶/溶酶体为靶点的药物来防治肥胖及相关代谢疾病提供了理论依据。