دورية أكاديمية
An anti-ANGPTL3/8 antibody decreases circulating triglycerides by binding to a LPL-inhibitory leucine zipper-like motif.
العنوان: | An anti-ANGPTL3/8 antibody decreases circulating triglycerides by binding to a LPL-inhibitory leucine zipper-like motif. |
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المؤلفون: | Balasubramaniam D; Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, IN, USA., Schroeder O; Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, IN, USA., Russell AM; Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, IN, USA., Fitchett JR; Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, IN, USA., Austin AK; Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, IN, USA., Beyer TP; Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, IN, USA., Chen YQ; Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, IN, USA., Day JW; Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, IN, USA., Ehsani M; Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, IN, USA., Heng AR; Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, IN, USA., Zhen EY; Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, IN, USA., Davies J; Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, IN, USA., Glaesner W; Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, IN, USA., Jones BE; Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, IN, USA., Siegel RW; Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, IN, USA., Qian YW; Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, IN, USA., Konrad RJ; Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, IN, USA. Electronic address: konrad_robert@lilly.com. |
المصدر: | Journal of lipid research [J Lipid Res] 2022 May; Vol. 63 (5), pp. 100198. Date of Electronic Publication: 2022 Mar 17. |
نوع المنشور: | Journal Article |
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: | Lipoprotein Lipase*/metabolism , Peptide Hormones*/metabolism, Angiopoietin-Like Protein 3 ; Angiopoietin-Like Protein 8 ; Angiopoietin-like Proteins/metabolism ; Apolipoprotein A-V ; Epitopes ; Humans ; Leucine Zippers ; Triglycerides/metabolism |
مستخلص: | Triglycerides (TG) are required for fatty acid transport and storage and are essential for human health. Angiopoietin-like-protein 8 (ANGPTL8) has previously been shown to form a complex with ANGPTL3 that increases circulating TG by potently inhibiting LPL. We also recently showed that the TG-lowering apolipoprotein A5 (ApoA5) decreases TG levels by suppressing ANGPTL3/8-mediated LPL inhibition. To understand how LPL binds ANGPTL3/8 and ApoA5 blocks this interaction, we used hydrogen-deuterium exchange mass-spectrometry and molecular modeling to map binding sites of LPL and ApoA5 on ANGPTL3/8. Remarkably, we found that LPL and ApoA5 both bound a unique ANGPTL3/8 epitope consisting of N-terminal regions of ANGPTL3 and ANGPTL8 that are unmasked upon formation of the ANGPTL3/8 complex. We further used ANGPTL3/8 as an immunogen to develop an antibody targeting this same epitope. After refocusing on antibodies that bound ANGPTL3/8, as opposed to ANGPTL3 or ANGPTL8 alone, we utilized bio-layer interferometry to select an antibody exhibiting high-affinity binding to the desired epitope. We revealed an ANGPTL3/8 leucine zipper-like motif within the anti-ANGPTL3/8 epitope, the LPL-inhibitory region, and the ApoA5-interacting region, suggesting the mechanism by which ApoA5 lowers TG is via competition with LPL for the same ANGPTL3/8-binding site. Supporting this hypothesis, we demonstrate that the anti-ANGPTL3/8 antibody potently blocked ANGPTL3/8-mediated LPL inhibition in vitro and dramatically lowered TG levels in vivo. Together, these data show that an anti-ANGPTL3/8 antibody targeting the same leucine zipper-containing epitope recognized by LPL and ApoA5 markedly decreases TG by suppressing ANGPTL3/8-mediated LPL inhibition. Competing Interests: Conflict of interest The authors declare that they have no conflicts of interest with the contents of this article. (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.) |
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فهرسة مساهمة: | Keywords: angiopoietin-like protein (ANGPTL); apolipoprotein (Apo); epitopes; hydrogen-deuterium exchange mass spectrometry (HDXMS); leucine zipper; lipoprotein lipase (LPL); molecular modeling; nano-imaging; transmission electron microscopy (TEM); triglycerides (TG) |
المشرفين على المادة: | 0 (ANGPTL3 protein, human) 0 (ANGPTL8 protein, human) 0 (Angiopoietin-Like Protein 3) 0 (Angiopoietin-Like Protein 8) 0 (Angiopoietin-like Proteins) 0 (Apolipoprotein A-V) 0 (Epitopes) 0 (Peptide Hormones) 0 (Triglycerides) EC 3.1.1.34 (Lipoprotein Lipase) |
تواريخ الأحداث: | Date Created: 20220321 Date Completed: 20220524 Latest Revision: 20220716 |
رمز التحديث: | 20231215 |
مُعرف محوري في PubMed: | PMC9036128 |
DOI: | 10.1016/j.jlr.2022.100198 |
PMID: | 35307397 |
قاعدة البيانات: | MEDLINE |
تدمد: | 1539-7262 |
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DOI: | 10.1016/j.jlr.2022.100198 |