FAT/CD36新型脂质配体对非酒精性脂肪肝的保护作用及机理研究

FAT / CD36 receptor recognition and transport for LCFA and oxLDL, and sterol regulatory element binding proteins（SREBPs）increase TG and TC synthetic are important pathological events of NAFLD. It seems is essential for targeted competition binding FAT / CD36 and.regulation SREBP-1c and SREBP-2 lipid synthesis in early protection of NAFLD. Our latest research reported a small molecule Lead compounds-OXL01 in ω-COOH group active center which could specifically bind FAT / CD36 to forming a stable lowest energy combination . It can inhibited the gene and protein expression of SREBP-1c and SREBP-2 and its downstream target genes in vitro. It can also significantly reduced triglyceride and cholesterol in HepG2 cell and C57BL/6 mice when treated with OXL01 chronically. It is very important that all of them imply OXL01 may is an affinity ligand of FAT / CD36, and OXL01 reduced triglyceride and cholesterol by suppressing pathway of FAT / CD36 and its downstream gene. This paper intends to research the binding relationship the OXL01 and FAT / CD36, and the OXL01 regulating molecular mechanism of lipid disorder by pathway of SREBPs and downstream target genes. Explore the biological protective effects of OXL01 in NAFLD.

FAT/CD36受体识别转运LCFA和oxLDL、SREBPs上调TG和TC合成途径，是NAFLD脂质代谢异常发生的关键病理环节。寻求靶向竞争结合FA/CD36，调控SREBP-1c 和SREBP-2脂质合成，实施NAFLD早期干预保护至关重要。前期研究发现并报道小分子先导化合物（OXL01）以ω-COOH基团为活性中心与FAT/CD36形成分子稳定最低能量结合；下调SREBP-1c 和SREBP-2及其下游靶基因表达；显著降低C57BL/6小鼠肝脏TG和TC异位沉积。提示OXL01可能以亲和配体形式作用于FAT/CD36及其下游途径，特异性调控脂质合成途径达到降脂作用的重要意义。本课题拟运用FAT/CD36及其下游基因过表达、siRNA和慢病毒注射，研究OXL01与FAT/CD36的结合关系以及调控SREBPs及其下游靶基因失稳态分子机理，探讨OXL01的NAFLD生物学保护作用。

NAFLD脂质代谢紊乱导致长链脂肪酸LCFA活化 清道夫受体FAT/CD36，招募Caveolin，PPAR-γ和LXR-α协同诱导FAT/CD36基因表达上调，进而上调SREBP-1c和SREBP-2及其下游基因表达，过量脂肪酸酯化和聚集，促进TG和TC大量病理性沉积和炎症进展，是NAFLD脂质代谢病理过程中的一个重要网络调控体系。抑制FAT/CD36受体识别LCFA和oxLDL，进而抑制肝脏脂质异位沉积形成一直被认为是预防和治疗NAFLD的最有效途径和关键药物靶点。.本课题运用FAT/CD36及其下游基因过表达、siRNA和慢病毒注射，从长链脂肪酸转运途径研究先导化合物OXL01与清道夫受体蛋白FAT/CD36的分子模拟结合、分子细胞动态结合和体内生理病理作用，确立了OXL01抑制FAT/CD36转运LCFA和oxLDL的膜相机理；发现先导化合物OXL01特异性靶向结合FAT/CD36，招募蛋白信号群Caveolin-1和2形成小窝蛋白Caveolins进行转运；同时OXL01经由FAT/CD36招募Fyn和 Lyn，启动调控PPAR-γ和LXR-α协同作用，调控SREBPs及其下游靶基因在长链脂肪酸和oxLDL所致失稳态分子机理，获得OXL01的NAFLD生物学保护作用机理，为OXL01靶向FAT/CD36治疗保护NAFLD药理学机理提供新理论基础。