BACKGROUND Familial hypercholesterolemia(FH)is a common autosomal dominant hereditary disease.Its early diagnosis and intervention significantly improve the patient’s quality of life.However,there are few types of re...BACKGROUND Familial hypercholesterolemia(FH)is a common autosomal dominant hereditary disease.Its early diagnosis and intervention significantly improve the patient’s quality of life.However,there are few types of research on the FH pathogenic genes in China.METHODS In this study,we recruited a family diagnosed with FH and used whole exome sequencing(WES)to analyze the proband variants.Intracellular cholesterol level,reactive oxygen species(ROS)level,and the expression of pyroptosis-related genes were detected after overexpression of wild-type or variant LDLR in L02 cells.RESULTS A heterozygous missense variant predicted to be deleterious to LDLR(c.1879G>A,p.Ala627Thr)was identified in the proband.Mechanistically,intracellular cholesterol level,ROS level,and the expression of pyroptosis-related genes,nucleotidebinding oligomerization domain-like receptor family protein 3(NLRP3)inflammasome and components(caspase 1,apoptosis-associated speck-like protein containing a caspase recruitment domain(ASC)and NLRP3),gasdermin D(GSDMD),interleukin(IL)-18,IL-1βwas elevated in the variant LDLR group,which was attenuated by inhibition of ROS.CONCLUSIONS FH is associated with a variant(c.1879G>A,p.Ala627Thr)in the LDLR gene.Regarding the mechanism,the ROS/NLRP3-mediated pyroptosis in hepatic cells may contribute to the pathogenesis of the LDLR variant.展开更多
[目的]综述新近发现的IDOL蛋白(Inducibledegrader of the low-density lipoprotein receptor)对低密度脂蛋白受体(low-densitylipoprotein receptor,LDLR)调节作用及肝X受体(LXR)-IDOL-LDLR轴在脂代谢平衡稳态中作用的研究进展。[方法...[目的]综述新近发现的IDOL蛋白(Inducibledegrader of the low-density lipoprotein receptor)对低密度脂蛋白受体(low-densitylipoprotein receptor,LDLR)调节作用及肝X受体(LXR)-IDOL-LDLR轴在脂代谢平衡稳态中作用的研究进展。[方法]查阅近年来国内外研究IDOL及LXRIDOL通路的相关文献,并归纳总结其在脂代谢中的作用。[结果]IDOL能在转录后水平介导LDLR及其家族其他成员(VLDLR、ApoER2)的泛素化降解,该作用独立于固醇调节元件结合蛋白(SREBP)途径且受LXR的调节。[结论]LXR-IDOL通路能通过IDOL依赖途径泛素化降解LDLR,调节LDLR水平及LDL摄取,从而在脂代谢平衡中发挥重要作用。LXR-IDOL-LDLR轴可能为脂质代谢紊乱及心血管疾病提供新的潜在治疗靶点。展开更多
基金supported by the Health and Family Planning Commission of Wuhan City(Grant Number WX18M02)Central Guiding Local Science and Technology Development Special Project(No.2022BGE272).
文摘BACKGROUND Familial hypercholesterolemia(FH)is a common autosomal dominant hereditary disease.Its early diagnosis and intervention significantly improve the patient’s quality of life.However,there are few types of research on the FH pathogenic genes in China.METHODS In this study,we recruited a family diagnosed with FH and used whole exome sequencing(WES)to analyze the proband variants.Intracellular cholesterol level,reactive oxygen species(ROS)level,and the expression of pyroptosis-related genes were detected after overexpression of wild-type or variant LDLR in L02 cells.RESULTS A heterozygous missense variant predicted to be deleterious to LDLR(c.1879G>A,p.Ala627Thr)was identified in the proband.Mechanistically,intracellular cholesterol level,ROS level,and the expression of pyroptosis-related genes,nucleotidebinding oligomerization domain-like receptor family protein 3(NLRP3)inflammasome and components(caspase 1,apoptosis-associated speck-like protein containing a caspase recruitment domain(ASC)and NLRP3),gasdermin D(GSDMD),interleukin(IL)-18,IL-1βwas elevated in the variant LDLR group,which was attenuated by inhibition of ROS.CONCLUSIONS FH is associated with a variant(c.1879G>A,p.Ala627Thr)in the LDLR gene.Regarding the mechanism,the ROS/NLRP3-mediated pyroptosis in hepatic cells may contribute to the pathogenesis of the LDLR variant.
文摘[目的]综述新近发现的IDOL蛋白(Inducibledegrader of the low-density lipoprotein receptor)对低密度脂蛋白受体(low-densitylipoprotein receptor,LDLR)调节作用及肝X受体(LXR)-IDOL-LDLR轴在脂代谢平衡稳态中作用的研究进展。[方法]查阅近年来国内外研究IDOL及LXRIDOL通路的相关文献,并归纳总结其在脂代谢中的作用。[结果]IDOL能在转录后水平介导LDLR及其家族其他成员(VLDLR、ApoER2)的泛素化降解,该作用独立于固醇调节元件结合蛋白(SREBP)途径且受LXR的调节。[结论]LXR-IDOL通路能通过IDOL依赖途径泛素化降解LDLR,调节LDLR水平及LDL摄取,从而在脂代谢平衡中发挥重要作用。LXR-IDOL-LDLR轴可能为脂质代谢紊乱及心血管疾病提供新的潜在治疗靶点。
