鱼类脂肪分解供能关键过程及其代谢调控机制研究

鱼类是重要的水产动物类群。提高养殖鱼类对脂肪的分解供能效率，是解决当前水产业优质饲料蛋白源紧缺、鱼体脂肪沉积严重等瓶颈问题的重要途径之一。鱼类脂肪分解供能的关键过程是游离脂肪酸（FFA）的产生和分解供能，其中包含脂滴水解和自噬、线粒体和过氧化物酶体β-氧化两对互相协作的代谢路径，然而此过程及其调控体系尚未得到深入研究。本项目拟以重要水产鱼类罗非鱼为主要研究对象，对此过程的代谢细节和调控机制开展深入研究。本项目将综合采用基因编辑、分子示踪、原位杂交、细胞转染等现代生物学技术，结合色谱-质谱、核磁成像等化学测量和组学数据分析，从在体和离体两个层面，对正常鱼/细胞和靶标代谢通路受限的实验鱼/细胞的FFA产生和分解过程进行解析，同时筛选出具备调控功能的核受体元件、内分泌和营养因子，并阐明相关的调控机制。本研究将完善现有的鱼类脂肪分解代谢知识体系，为鱼类脂质营养代谢的高效人工调控打下坚实的理论基础。

Fish is one of the most important aquaculture species. In the current aquaculture, the shortage of dietary high quality protein sources, such fish meal, and the severe lipid accumulation in farmed fish have been serious bottleneck problems for the sustainable development of aquaculture. The promotion of lipid catabolism for energy production in fish will be largely helpful to increase dietary protein efficiency (protein sparing effect) and decrease body lipid deposit in farmed fish, thus this has attracted high attentions in global fish nutritionists. However, the detailed biological process and the related regulatory mechanisms of lipid catabolism have not been well studied in fish. In the lipid catabolism, the key process is the production and breakdown of free fatty acids (FFA) sourced from exogenous and endogenous triglycerides (TG). This process mainly includes lipolysis and lipophagy, and mitochondrial and peroxisomal β-oxidation as two pairs of interacting metabolic progresses. The applicant has concentrated in lipid catabolism study for 16 years and is rich of research experiences in the molecular and cell biology of lipid metabolism. In the present proposal, the applicant plans to use Nile tilapia, which is one of the most important economic fish species, as the main research model, and also use zebrafish as supplemental model, to investigate the biological process and the related regulatory mechanisms of lipolysis, lipophagy, and mitochondrial and peroxisomal β-oxidation, and their interaction, in order to illustrate the biological mechanisms of the production and β-oxidation of FFA sourced from triglycerides. A series of molecular and cellular techniques, such as CRISPR/Cas9, RNAi, molecular tracking, transfection, combined with modern analytical chemical measurements, such as LC/MS, NMR, MRI, would be used. Several “-omics” studies would also be applied to understand the systemic gene regulating network in the FFA metabolism. Normal and gene KO fish would be applied for the in vivo and in vitro studies, and a number of nuclear receptors, endocrinological and nutritional factors, which could regulate the FFA metabolism, would be selected and the related regulating mechanisms would be explored, respectively. The results from the present study would be helpful to understand the precise biological process of lipid catabolism and could be important knowledge base for the artificial regulation of lipid metabolism in farmed fish in future.