An anti-ANGPTL3/8 antibody decreases circulating triglycerides by binding to a LPL-inhibitory leucine zipper-like motif.

Autor:	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.
Jazyk:	angličtina
Zdroj:	Journal of lipid research [J Lipid Res] 2022 May; Vol. 63 (5), pp. 100198. Date of Electronic Publication: 2022 Mar 17.
DOI:	10.1016/j.jlr.2022.100198
Abstrakt:	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.)
Databáze:	MEDLINE
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