دورية أكاديمية
أعرض في EDS

Cell-associated heparin-like molecules modulate the ability of LDL to regulate PCSK9 uptake.

التفاصيل البيبلوغرافية
العنوان: Cell-associated heparin-like molecules modulate the ability of LDL to regulate PCSK9 uptake.
المؤلفون: Galvan AM; Department of Cellular and Molecular Pharmacology and Howard Hughes Medical Institute, University of California San Francisco, San Francisco, CA 94143., Chorba JS; Division of Cardiology, Zuckerberg San Francisco General, Department of Medicine, University of California San Francisco, San Francisco, CA 94110 john.chorba@ucsf.edu.
المصدر: Journal of lipid research [J Lipid Res] 2019 Jan; Vol. 60 (1), pp. 71-84. Date of Electronic Publication: 2018 Nov 21.
نوع المنشور: Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't
اللغة: English
بيانات الدورية: Publisher: Elsevier Country of Publication: United States NLM ID: 0376606 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1539-7262 (Electronic) Linking ISSN: 00222275 NLM ISO Abbreviation: J Lipid Res Subsets: MEDLINE
أسماء مطبوعة: Publication: 2021- : [New York] : Elsevier
Original Publication: Memphis, Lipid Research, inc.
مواضيع طبية MeSH: Heparin/*metabolism , Lipoproteins, LDL/*metabolism , Proprotein Convertase 9/*metabolism, Gene Expression Regulation/drug effects ; HEK293 Cells ; Hep G2 Cells ; Heparin Lyase/metabolism ; Humans ; Lipoproteins, LDL/pharmacology ; Protein Transport/drug effects ; Receptors, LDL/metabolism
مستخلص: Proprotein convertase subtilisin/kexin type 9 (PCSK9) targets the LDL receptor (LDLR) for degradation, increasing plasma LDL and, consequently, cardiovascular risk. Uptake of secreted PCSK9 is required for its effect on the LDLR, and LDL itself inhibits this uptake, though how it does so remains unclear. In this study, we investigated the relationship between LDL, the PCSK9:LDLR interaction, and PCSK9 uptake. We show that LDL inhibits binding of PCSK9 to the LDLR in vitro more impressively than it inhibits PCSK9 uptake in cells. Furthermore, cell-surface heparin-like molecules (HLMs) can partly explain this difference, consistent with heparan sulfate proteoglycans (HSPGs) acting as coreceptors for PCSK9. We also show that HLMs can interact with either PCSK9 or LDL to modulate the inhibitory activity of LDL on PCSK9 uptake, with such inhibition rescued by competition with the entire PCSK9 prodomain, but not its truncated variants. Additionally, we show that the gain-of-function PCSK9 variant, S127R, located in the prodomain near the HSPG binding site, exhibits increased affinity for HLMs, potentially explaining its phenotype. Overall, our findings suggest a model where LDL acts as a negative regulator of PCSK9 function by decreasing its uptake via direct interactions with either the LDLR or HLMs.
(Copyright © 2019 Galvan and Chorba.)
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معلومات مُعتمدة: K08 HL124068 United States HL NHLBI NIH HHS
فهرسة مساهمة: Keywords: atherosclerosis; cholesterol; coreceptor; dyslipidemias; familial hypercholesterolemia; lipoprotein metabolism; low density lipoprotein; low density lipoprotein receptor; mechanism; proprotein convertase subtilisin/kexin type 9; receptors/lipoprotein; single nucleotide polymorphism
المشرفين على المادة: 0 (Lipoproteins, LDL)
0 (Receptors, LDL)
9005-49-6 (Heparin)
EC 3.4.21.- (Proprotein Convertase 9)
EC 4.2.2.7 (Heparin Lyase)
تواريخ الأحداث: Date Created: 20181123 Date Completed: 20200210 Latest Revision: 20210217
رمز التحديث: 20221213
مُعرف محوري في PubMed: PMC6314249
DOI: 10.1194/jlr.M087189
PMID: 30463987
قاعدة البيانات: MEDLINE
الوصف
تدمد:1539-7262
DOI:10.1194/jlr.M087189