Bezafibrate促进肉碱棕榈酰基转移酶Ⅱ缺陷症能量代谢的作用机制研究

CPT Ⅱ缺陷症是一种常见的遗传性代谢病，其缺陷直接导致线粒体脂肪酸β-氧化紊乱，能量代谢障碍，但其发病机理至今未完全明确，尤其是对CPT Ⅱ缺陷症病人的临床药物治疗研究未有深入。我们通过转染COS-7细胞发现变异的CPT Ⅱ表现为酶活性降低和热不稳定性、蛋白半衰期缩短、脂肪酸β-氧化和ATP生成不足。我们对CPT Ⅱ缺陷症进行基因组序列分析并获得了CPT Ⅱ缺陷症细胞系，用Fibrate类降血脂药处理CPT Ⅱ缺陷症细胞，研究发现Bezafibrate能显著提高CPT Ⅱ残基酶活性及脂肪酸代谢相关基因的表达。我们拟进一步用Bezafibrate处理CPT Ⅱ缺陷症细胞和CPT Ⅱ点突变小鼠，分析脂肪酸β-氧化和ATP生成变化，从细胞水平和动物整体水平阐明其促进CPT Ⅱ缺陷症能量代谢的分子机制。该研究的深入有望进一步揭示CPT Ⅱ缺陷症病人的发病机理，并为临床药物治疗研究提供基本数据。

Carnitine palmitoyltransferase Ⅱ (CPT Ⅱ) deficiency is one of the most common inherited metabolic diseases characterized by myalgia, exercise intolerance and rhabdomyolysis, which is a rare autosomal recessive inheritance. It results in mitochondrial long-chain fatty acid β-oxidation (FAO) disorder and energy crisis. Although numerous studies had been carried out on these dieases, but the precise molecular mechanisms of CPT Ⅱ deficiency were not completely understood, especially the studies of the clinical treatment on CPT Ⅱ deficiency patients had no further progress. In our previous study, we reported the variants CPT Ⅱ performed reduced residue enzyme activity, thermal instability, short half-life, decreased fatty acid β-oxidation, low ATP production and loss of mitochondrial membrane potential in transfected COS-7 cells. Recently, we cultured CPT Ⅱ deficiency patients fibroblast and analyzed their genomics DNA sequence, treated fibroblasts with fibrate group of hypolipidemic drugs. The data indicated that the Bezafibrate significantly improve the CPT Ⅱ residue enzyme activity and the fatty acid β-oxidation related genes expression. In this study, we intends to further analyze the energy crisis of treatment with Bezafibrate in CPT Ⅱ deficiency cells and CPT Ⅱ point mutant mice. Clarify fatty acid β-oxidation and ATP production levels, and further elucidate the molecular mechanisms of Bezafibrate up-regulated energy crisis in CPT Ⅱ deficiency cells and animal models. The study will further reveals the pathogenesis of CPT Ⅱ deficiency patients and provides the basic data for clinical research of drug therapy.