1.Progress on association between low-density lipoprotein receptor and metabolic syndrome.
Journal of Zhejiang University. Medical sciences 2015;44(1):101-107
Low-density lipoprotein receptor (LDLR) and metabolic syndrome (MS) are closely correlated. Changes in LDLR expression, feedback regulation and degradation, impacts of LDLR deficiency on blood lipid levels, roles of LDLR in islet β cell dysfunction and cholesterol homeostasis dysregulation, expression of LDLR gene nuclear transcription factors and polymorphism of LDLR gene segments are all involved in the development of specific components of MS. In recent years, a variety of targets and intervention mechanisms in relation to LDLR and MS have been extensively studied. Knowledge about association between LDLR and MS may contribute to the development of strategies for prevention and treatment of MS. This article reviews the update on the association between LDLR and MS.
Homeostasis
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Humans
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Lipid Metabolism
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Lipoproteins, LDL
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Metabolic Syndrome
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Receptors, LDL
2.Genetic analysis of a patient with familial hypercholesterolemia due to variant of LDLR gene.
Guanxiong WANG ; Liting LIU ; Yang GAO ; Mingrong LYU ; Huan WU ; Xiaojin HE
Chinese Journal of Medical Genetics 2023;40(4):458-461
OBJECTIVE:
To analyze variant of LDLR gene in a patient with familial hypercholesterolemia (FH) in order to provide a basis for the clinical diagnosis and genetic counseling.
METHODS:
A patient who had visited the Reproductive Medicine Center of the First Affiliated Hospital of Anhui Medical University in June 2020 was selected as the study subject. Clinical data of the patient was collected. Whole exome sequencing (WES) was applied to the patient. Candidate variant was verified by Sanger sequencing. Conservation of the variant site was analyzed by searching the UCSC database.
RESULTS:
The total cholesterol level of the patient was increased, especially low density lipoprotein cholesterol. A heterozygous c.2344A>T (p.Lys782*) variant was detected in the LDLR gene. Sanger sequencing confirmed that the variant was inherited from the father.
CONCLUSION
The heterozygous c.2344A>T (p.Lys782*) variant of the LDLR gene probably underlay the FH in this patient. Above finding has provided a basis for genetic counseling and prenatal diagnosis for this family.
Humans
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Cholesterol, LDL/genetics*
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Heterozygote
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Hyperlipoproteinemia Type II/genetics*
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Mutation
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Pedigree
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Phenotype
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Receptors, LDL/genetics*
3.Analysis of clinical phenotypes and variants of LDLR gene in two Chinese patients with familial hypercholesterolemia.
Kexin WANG ; Tao SUN ; Xiaoping ZHANG ; Yahui ZHANG ; Hai GAO ; Yanlong REN ; Xiaoyan LI
Chinese Journal of Medical Genetics 2022;39(12):1344-1348
OBJECTIVE:
To explore the correlation between clinical phenotypes and pathogenic variants in two patients with familial hypercholesterolemia.
METHODS:
Both patients were subjected to whole exome sequencing (WES) with a focus on the analysis of genes associated with dyslipidemia. Candidate variants were verified by Sanger sequencing of the patients and their family members.
RESULTS:
WES revealed that the proband 1 has harbored two heterozygous variants of the LDLR gene, namely c.1360G>A (p.D454N) and c.292G>A (p.G98S), whilst proband 2 has harbored a heterozygous c.321T>G (p.C107W) variant of the LDLR gene. Based on the guidelines from the American College of Medical Genetic and Genomics (ACMG), the above variants were respectively predicted to be likely pathogenic (PM1+PM2+PP2+PP3+PP4+PP5), variant of unknown significance (PM1+PP2+PP3), and likely pathogenic (PM1+PM2+PP2+PP4+PP5). Treatment with PCSK9 inhibitor has attained a significant effect in proband 1 but no apparent effect in proband 2.
CONCLUSION
Variants of the LDLR gene probably underlay the familial hypercholesterolemia in the two pedigrees. The difference in the severity of the clinical phenotypes and response to PCSK9 inhibitor treatment between the two probands may be attributed to the different genotypes of the LDLR gene. Genetic testing not only can provide a basis for clinical diagnosis, but also facilitate the choice of lipid-lowering drugs.
Humans
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China
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Hyperlipoproteinemia Type II/genetics*
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Phenotype
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Receptors, LDL/genetics*
5.Molecular mechanism of astragaloside Ⅳ against atherosclerosis by regulating miR-17-5p and PCSK9/VLDLR signal pathway.
He-Wei QIN ; Qin-Sheng ZHANG ; Yan-Jie LI ; Wen-Tao LI ; Yuan WANG
China Journal of Chinese Materia Medica 2022;47(2):492-498
This study explores the regulatory effect of astragaloside Ⅳ on miR-17-5 p and its downstream proprotein convertase subtillisin/kexin type 9(PCSK9)/very low density lipoprotein receptor(VLDLR) signal pathway, aiming at elucidating the mechanism of astragaloside Ⅳ against atherosclerosis(AS). In cell experiment, oxidized low-density lipoprotein(ox-LDL) was used for endothelial cell injury modeling with vascular smooth muscle cells(VSMCs). Then cells were classified into the model group, miR-17-5 p inhibitor group, blank serum group, and astragaloside Ⅳ-containing serum group based on the invention. Afterward, cell viability and the expression of miR-17-5 p, VLDLR, and PCSK9 mRNA and protein in cells in each group were detected. In animal experiment, 15 C57 BL/6 mice were used as the control group, and 45 ApoE~(-/-) mice were classified into the model group, miR-17-5 p inhibitor group, and astragaloside Ⅳ group, with 15 mice in each group. After 8 weeks of intervention, the peripheral serum levels of interleukin-6(IL-6), interleukin-10(IL-10), and tumor necrosis factor-α(TNF-α), and the expression of miR-17-5 p, VLDLR, and PCSK9 mRNA in the aorta of mice were detected. The pathological changes of mice in each group were observed. According to the cell experiment, VSMC viability in the miR-17-5 p inhibitor group and the astragaloside Ⅳ-containing serum group was higher than that in the model group(P<0.05). The mRNA and protein expression of miR-17-5 p and VLDLR in VSMCs in the miR-17-5 p inhibitor group and the astragaloside Ⅳ-containing serum group was lower than that in the model group(P<0.05), but the mRNA and protein expression of PCSK9 was higher than that in the model group(P<0.05). As for the animal experiment, the levels of IL-6 and TNF-α in the peripheral serum of the miR-17-5 p inhibitor group and the astragaloside Ⅳ group were lower(P<0.05) and the serum level of IL-10 was higher(P<0.05) than that of the model group. The mRNA expression of miR-17-5 p and VLDLR in the aorta in the miR-17-5 p inhibitor group and the astragaloside Ⅳ group was lower(P<0.05), and PCSK9 mRNA expression was higher(P<0.05) than that in the model group. Pathological observation showed mild AS in the miR-17-5 p inhibitor group and the astragaloside Ⅳ group. In summary, astragaloside Ⅳ can prevent the occurrence and development of AS. The mechanism is that it performs targeted regulation of miR-17-5 p, further affecting the PCSK9/VLDLR signal pathway, inhibiting vascular inflammation, and thus alleviating endothelial cell injury.
Animals
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Atherosclerosis/genetics*
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Lipoproteins, LDL/metabolism*
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Mice
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MicroRNAs/metabolism*
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Proprotein Convertase 9/metabolism*
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Receptors, LDL/metabolism*
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Saponins
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Signal Transduction
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Triterpenes
6.Preparation and characterization of polyclonal antibodies against VLDL receptor.
Shen QU ; Tao CHEN ; Fan WU ; Yanhua YIN ; Hao BI
Journal of Huazhong University of Science and Technology (Medical Sciences) 2004;24(3):205-207
The polyclonal antibodies against VLDL receptor were prepared and identified. Rabbits were immunized with polypeptide fragment of VLDL receptor as antigen. The collected blood serum of the immunized rabbits was analyzed and identified by using ELISA and Western Blot. The results showed that the rabbit against mouse and human VLDL receptor antibodies were obtained with high titer and could recognize the natural VLDL receptors through Western blot. The prepared polyclonal antibodies against VLDL receptor provide a new tool to study the protein of VLDL receptor.
Animals
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Antibodies
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chemistry
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immunology
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Enzyme-Linked Immunosorbent Assay
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Female
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Humans
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Peptides
;
immunology
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Rabbits
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Receptors, LDL
;
immunology
7.Ubiquitin Ligases in Cholesterol Metabolism.
Diabetes & Metabolism Journal 2014;38(3):171-180
To maintain cholesterol homeostasis, the processes of cholesterol metabolism are regulated at multiple levels including transcription, translation, and enzymatic activity. Recently, the regulation of protein stability of some key players in cholesterol metabolism has been characterized. More and more ubiquitin ligases have been identified including gp78, Hrd1, TRC8, TEB4, Fbw7, and inducible degrader of low density lipoprotein receptor. Their working mechanisms and physiological functions are becoming revealed. Here, we summarize the structure, substrates and function of these ubiquitin ligases. Their potential application in drug discovery is also discussed.
Cholesterol*
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Drug Discovery
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Homeostasis
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Ligases*
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Metabolism*
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Protein Stability
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Receptors, LDL
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Ubiquitin*
8.Functional analysis of low-density lipoprotein receptor in homozygous familial hypercholesterolemia patients with novel 1439 C-->T mutation of low-density lipoprotein receptor gene.
Jie LIN ; Lu-ya WANG ; Shu LIU ; Jun-hui XIA ; Qiang YONG ; Lan-ping DU ; Xiao-dong PAN ; Hong XUE ; Bao-sheng CHEN ; Zhi-sheng JIANG
Chinese Medical Journal 2008;121(9):776-781
BACKGROUNDFamilial hypercholesterolemia (FH), caused by low density lipoprotein (LDL) receptor (LDL-R) gene mutations, is associated with increased risk of premature coronary heart disease. Until now, limited molecular data concerning FH are available in China. The present study described the clinical profiles and cell biological defects of a Chinese FH kindred with novel LDL-R gene mutation.
METHODSThe patient's LDL-R gene coding region was sequenced. The patient's lymphocytes were isolated and the LDL-R expression, binding and up-take functions were observed by immunohistochemistry staining and flow cytometry detection. The patient's heart and the major large vessels were detected by vessel ultrasound examination and myocardial perfusion imaging (MPI).
RESULTSThe patient's LDL-R expression, LDL binding and up-take functions were significantly lower than normal control (39%, 63% and 76% respectively). A novel homozygous 1439 C-->T mutation of the LDL-R gene was detected in the patient and his family. ECG showed atypical angina pectoris. Echocardiogram showed stenosis of the coronary artery and calcification of the aortic valve and its root. Blood vessel ultrasound examination showed the thickness of large vessel intima, and the vessel lumen was narrowed by 71%. MPI showed ischemic changes.
CONCLUSIONSThe LDL-R synthesis dysfunction of FH patients leads to arterial stenosis and calcification, which are the major phenotype of the clinical disorder. The mutation of the LDL-R gene is determined. These data increase the mutational spectrum of FH in China.
Adult ; Child, Preschool ; Homozygote ; Humans ; Hyperlipoproteinemia Type II ; genetics ; Middle Aged ; Mutation ; Receptors, LDL ; genetics ; physiology
9.Preparation and characterization of polyclonal antibodies against VLDL receptor.
Shen, QU ; Tao, CHEN ; Fan, WU ; Yanhua, YIN ; Hao, BI
Journal of Huazhong University of Science and Technology (Medical Sciences) 2004;24(3):205-7
The polyclonal antibodies against VLDL receptor were prepared and identified. Rabbits were immunized with polypeptide fragment of VLDL receptor as antigen. The collected blood serum of the immunized rabbits was analyzed and identified by using ELISA and Western Blot. The results showed that the rabbit against mouse and human VLDL receptor antibodies were obtained with high titer and could recognize the natural VLDL receptors through Western blot. The prepared polyclonal antibodies against VLDL receptor provide a new tool to study the protein of VLDL receptor.
Antibodies/chemistry
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Antibodies/*immunology
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Enzyme-Linked Immunosorbent Assay
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Peptides/*immunology
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Receptors, LDL/*immunology
10.Screening of LDLR gene mutations in nine patients with familial hypercholesterolemia.
Xiaolu MENG ; Nuo SI ; Yuqi SHEN ; Qi WANG ; Jiangchun HE ; Chaoxiao LU ; Wei WU ; Shuyang ZHANG ; Xue ZHANG
Chinese Journal of Medical Genetics 2018;35(6):783-786
OBJECTIVE:
To screen for LDLR gene mutations in 9 patients with familial hypercholesterolemia (FH).
METHODS:
All exons of the LDLR gene and flanking intronic sequences were amplified by PCR and subjected to automatic DNA sequencing. For patients with homozygous or compound heterozygous mutations, parental DNA sequencing or T cloning sequencing was carried out to determine the parental origin of the mutant alleles.
RESULTS:
Direct sequencing of PCR products revealed 8 LDLR variants in 7 patients, which included c.259T>G, c.513delC, c.530C>T, c.682G>T, c.763C>T, c.1187-10G>A, c.1948delG, and c.1730G>A, among which c.1948delG was novel. Four patients have carried heterozygous mutations, two carried homozygous mutations, and one carried compound heterozygous mutations. The patients with biallelic mutations presented with a more severe phenotype compared those carrying heterozygous mutations.
CONCLUSION
LDLR mutations were identified in 7 out of 9 patients with FH. Among the 8 identified LDLR mutations, c.1948delG was firstly reported. Above findings have expanded the mutation spectrum of LDLR gene.
DNA Mutational Analysis
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Genetic Testing
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Humans
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Hyperlipoproteinemia Type II
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genetics
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Mutation
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Phenotype
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Receptors, LDL
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genetics