Molecular basis of familial hypercholesterolemia

Bruikman, Caroline S.; Hovingh, G. Kees; Kastelein, John J.P.

doi:10.1097/hco.0000000000000385

Cited by 29 publications

(15 citation statements)

References 46 publications

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“…Binding between the LDL receptor and apoB100 only occurs after the polypeptide has undergone a conformational change which results due to the lipolysis of VLDL to LDL [ 59 , 60 ]. Loss-of-function mutations in the LDL receptor or apoB can result in familial hypercholesterolemia, which is characterized by extremely elevated plasma LDL levels, thus leading to accelerated atherosclerosis [ 61 ]. Additionally, gain-of-function mutations in PCSK9, a proprotein convertase that accelerates the degradation of the LDL receptor, also results in high LDL concentrations [ 62 ].…”

Section: Apob: Characteristics and Compositionmentioning

confidence: 99%

Apolipoprotein B and Cardiovascular Disease: Biomarker and Potential Therapeutic Target

et al. 2021

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Apolipoprotein (apo) B, the critical structural protein of the atherogenic lipoproteins, has two major isoforms: apoB48 and apoB100. ApoB48 is found in chylomicrons and chylomicron remnants with one apoB48 molecule per chylomicron particle. Similarly, a single apoB100 molecule is contained per particle of very-low-density lipoprotein (VLDL), intermediate density lipoprotein, LDL and lipoprotein(a). This unique one apoB per particle ratio makes plasma apoB concentration a direct measure of the number of circulating atherogenic lipoproteins. ApoB levels indicate the atherogenic particle concentration independent of the particle cholesterol content, which is variable. While LDL, the major cholesterol-carrying serum lipoprotein, is the primary therapeutic target for management and prevention of atherosclerotic cardiovascular disease, there is strong evidence that apoB is a more accurate indicator of cardiovascular risk than either total cholesterol or LDL cholesterol. This review examines multiple aspects of apoB structure and function, with a focus on the controversy over use of apoB as a therapeutic target in clinical practice. Ongoing coronary artery disease residual risk, despite lipid-lowering treatment, has left patients and clinicians with unsatisfactory options for monitoring cardiovascular health. At the present time, the substitution of apoB for LDL-C in cardiovascular disease prevention guidelines has been deemed unjustified, but discussions continue.

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Section: Apob: Characteristics and Compositionmentioning

confidence: 99%

Apolipoprotein B and Cardiovascular Disease: Biomarker and Potential Therapeutic Target

et al. 2021

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“…Of these death numbers, roughly 7.4 million were due to coronary heart disease and 6.7 million were due to stroke (WHO, 2016 ). Hypercholesterolemia, one of the major risk factors for atherosclerosis and developing CVD, is characterized by high level of low density lipoprotein (LDL) cholesterol (LDL-C) in plasma (Newman et al, 1986 ; Lusis, 2000 ; Hopkins et al, 2011 ; Varghese, 2014 ; Bruikman et al, 2017 ). LDL particles are removed from the circulation mainly by hepatic uptake via the LDL receptor (LDLR).…”

Section: Introductionmentioning

confidence: 99%

Post-transcriptional Regulation of PCSK9 by miR-191, miR-222, and miR-224

et al. 2017

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Since proprotein convertase subtilisin kexin 9 (PCSK9) discovery, a gene involved in LDL metabolism regulation and cardiovascular diseases (CVD), many therapeutic strategies have been introduced for direct targeting of PCSK9. The main goal of these strategies has been to reduce PCSK9 protein level either by application of antibodies or inhibition of its production. In this study, we have tried to discover microRNAs (miRNAs) which can target, and hence regulate, PCSK9 expression. Using bioinformatics tools, we selected three microRNAs with binding sites on 3′-UTR of PCSK9. The expression level of these miRNAs was examined in three different cell lines using real-time RT-PCR. We observed a reciprocal expression pattern between expression level of miR-191, miR-222, and miR-224 with that of PCSK9. Accordingly, the expression levels were highest in Huh7 cells which expressed the lowest level of PCSK9, compared to HepG2 and A549 cell lines. PCSK9 mRNA level also showed a significant decline in HepG2 cells transfected with the vectors overexpressing the aforementioned miRNAs. Furthermore, the miRNAs target sites were cloned in psiCHECK-2 vector, and a direct interaction of the miRNAs and the PCSK9 3′-UTR putative target sites was investigated by means of luciferase assay. Our findings revealed that miR-191, miR-222, and miR-224 can directly interact with PCSK9 3′-UTR and regulate its expression. In conclusion, our data introduces a role for miRNAs to regulate PCSK9 expression.

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“…FH heterozygotes account for 1/20 of those presenting with early CAD and ~ 5% of myocardial infarctions (MIs) in persons below 60 years of age . It has been suggested that the prevalence of FH is 1 in 230–250 individuals and that < 1% of FH patients have been identified across the globe . FH heterozygote plasma cholesterol levels are twice as high as normal, resulting in distinctive cholesterol deposits (xanthomas) in tendons and skin.…”

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confidence: 99%

Endoplasmic reticulum quality control of LDLR variants associated with familial hypercholesterolemia

et al. 2019

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Loss‐of‐function mutations in the low‐density lipoprotein receptor (LDLR) gene can cause familial hypercholesterolemia (FH), but detailed functional evidence for pathogenicity is limited to a few reported mutations. Here, we investigated the cellular pathogenic mechanisms of three mutations in LDLR causing FH, which are structurally identical to pathogenic mutations in the very low‐density lipoprotein receptor (VLDLR). Similar to the VLDLR mutants, LDLR mutants D482H and C667F were found to be localized to the ER, while D445E, which is a conserved amino acid change, did not affect the trafficking of the receptor to the plasma membrane, as confirmed by the N‐glycosylation profile. Although the ER‐retained mutant proteins were soluble, induction of ER stress was observed as indicated by spliced X‐box binding protein‐1 (XBP‐1) mRNA levels. The mutants were found to associate with ER quality control components, and their stability was enhanced by inhibitors of proteasome. Our results contribute to the growing list of transport‐deficient class II LDLR variants leading to FH and provide evidence for the involvement of endoplasmic reticulum‐associated degradation in their stability.

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Molecular basis of familial hypercholesterolemia

Cited by 29 publications

References 46 publications

Apolipoprotein B and Cardiovascular Disease: Biomarker and Potential Therapeutic Target

Apolipoprotein B and Cardiovascular Disease: Biomarker and Potential Therapeutic Target

Post-transcriptional Regulation of PCSK9 by miR-191, miR-222, and miR-224

Endoplasmic reticulum quality control of LDLR variants associated with familial hypercholesterolemia

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