Identification of an LDLR variant in a Chinese familial hyper-cholesterolemia and its relation to ROS/NLRP3-Mediated pyroptosis in hepatic cells
Wen-Zhuo CHENG1
Wei-Hua WANG2
Ai-Ping DENG3
Xiao DANG4
Chao LIU5
Xian-Can WANG6
Ju-Yi LI3
Si JIN1
1.Department of Endocrinology,Institute of Geriatric Medicine,Liyuan Hospital,Tongji Medical College,Huazhong University of Science and Technology,Wuhan,Hubei,China2.Department of Party Affairs,Pulmonary and Critical Care Medicine,The Central Hospital of Wuhan,Tongji Medical College,Huazhong University of Science and Technology,Wuhan,Hubei,China3.Department of Pharmacy,Central Hospital of Wuhan,Tongji Medical College,Huazhong Uni-versity of Science and Technology,Wuhan,Hubei,China4.Department of Prenatal Diagnostic Center,Guangzhou Women and Children's Medical Center,Guangzhou Medical University,Guangdong,China5.Hubei Key Laboratory of Diabetes and Angiopathy,Hubei University of Science and Technology,Wuhan,Hubei,China6.Department of Car-diovascular Surgery,Central Hospital of Wuhan,Tongji Medical College,Huazhong University of Science and Techno-logy,Wuhan,Hubei,China
摘要：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 pathogen-ic 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,nucleotide-binding oligomerization domain-like receptor family protein 3(NLRP3)inflammasome and components(caspase 1,apoptosis-as-sociated speck-like protein containing a caspase recruitment domain(ASC)and NLRP3),gasdermin D(GSDMD),interleukin(IL)-18,IL-1β was 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.
机标关键词：pyroptosisidentificationrelationchinesevariantcellsldlrcholesterolemia
论文发表日期：2023-05-28
在线出版日期：2025-08-15（本平台首次上网日期，不代表文献的发表时间）
页数：9( 341-349 )