Identification of an LDLR variant in a Chinese familial hypercholesterolemia and its relation to ROS/NLRP3-Mediated pyroptosis in hepatic cells.
10.26599/1671-5411.2023.05.003
- Author:
Wen-Zhuo CHENG
1
;
Wei-Hua WANG
2
;
Ai-Ping DENG
3
;
Xiao DANG
4
;
Chao LIU
5
;
Xian-Can WANG
6
;
Ju-Yi LI
3
;
Si JIN
1
Author Information
1. Department of Endocrinology, Institute of Geriatric Medicine, Liyuan Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China.
2. 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, China.
3. Department of Pharmacy, Central Hospital of Wuhan, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China.
4. Department of Prenatal Diagnostic Center, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, Guangdong, China.
5. Hubei Key Laboratory of Diabetes and Angiopathy, Hubei University of Science and Technology, Wuhan, Hubei, China.
6. Department of Cardiovascular Surgery, Central Hospital of Wuhan, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China.
- Publication Type:Journal Article
- From:
Journal of Geriatric Cardiology
2023;20(5):341-349
- CountryChina
- Language:English
-
Abstract:
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, nucleotide-binding 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-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.
