脂蛋白脂肪酶(LPL)基因缺陷相关疾病与治疗进展

Lipoprotein Lipase(LPL)Gene Deficiency Related Diseases and Treatment Progress

脂蛋白脂肪酶(LPL)是人体脂蛋白中甘油三酯代谢的关键限速酶,由心肌、骨骼肌、脂肪细胞等实质细胞合成,分泌到细胞间隙与硫酸乙酰肝素蛋白多糖(HSPG)结合,在肝素的作用下解离,被毛细血管内皮细胞上的糖基化磷脂酰肌醇锚定高密度脂蛋白结合蛋白1(GPIHBP1)捕获转位入血,将血液中脂蛋白中核心甘油三酯水解,释放游离脂肪酸,供机体氧化利用或储存。其活性受多种互作蛋白调节,包括ApoCs、ANGPTLs、LMF1等。编码LPL的基因发生突变、蛋白合成加工过程出现错误或相关互作蛋白异常都会导致LPL缺失或功能异常,出现血脂升高或伴发胰腺炎等临床症状,严重威胁患者的生命健康。目前LPL缺陷相关疾病的临床常规治疗手段是降脂药与严格饮食控制相结合,治疗效果并不理想。近年来,以LPL及其互作蛋白基因为靶点的药物相继进入临床研究和上市阶段,取得了良好的临床效果,其中以基因替代、寡核苷酸和小RNA类药物最受关注。本综述结合LPL的特性、LPL缺乏症(LPLD)的病理机制,总结现有的治疗方法及药物研发进展,以期对LPLD的药物研发和医学干预提供思路。

Lipoprotein lipase(LPL)is an important rate-limiting enzyme in the metabolism of triglycerides in human lipoproteins.It is synthesized by parenchymal cells such as myocardium,skeletal muscle,and adipocytes,secreted into intercellular spaces,and binds to heparan sulfate proteoglycans(HSPG),and is dissociated under the action of heparin.It is captured and translocated into the blood by glycosylphosphatidylinositol-anchored high density lipoprotein-binding protein 1(GPIHBP1)on endothelial cells of capillaries,hydrolyzing the core triglycerides in lipoproteins in the blood,releasing free fatty acids for oxidation and utilization,or storage.LPL’s enzymatic activity is regulated by various interacting proteins,including ApoCs,ANGPTLs,LMF1,etc.Mutations in LPL-encoding gene,errors in protein synthesis and processing,or abnormalities in its interacting proteins can lead to LPL deficiency or dysfunction,cause clinical symptoms such as elevated blood lipids or pancreatitis,which seriously threatening the health of patients.At present,the routine clinical treatment for LPL deficiency related diseases is lipid-lowering drugs combined with strict dietary control,but the effect is not ideal.In recent years,drugs targeting LPL and its interacting protein genes have successively entered the stage of clinical research and marketing,and achieved good clinical effects.Among them,gene substitution,oligonucleotides,and small RNA drugs have been most concerned.Based on the characteristics of LPL and the pathologic mechanism of LPL deficiency(LPLD),the current therapeutic meth-ods and drug development progress were summarized in this review,so as to provide ideas for drug development and medical intervention of LPLD.