ArticleJournal of lipid research2022
An anti-ANGPTL3/8 antibody decreases circulating triglycerides by binding to a LPL-inhibitory leucine zipper-like motif.
Article in Journal of lipid research, 2022. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 28 papers.
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Who cites it
28 citing papers in PubMed, 46 citations in OpenAlex.
- Decreases in circulating ANGPTL3/8 concentrations following retatrutide treatment parallel reductions in serum lipids.Diabetes, obesity & metabolism · 2025Trial
- Targeting the angiopoietin-like protein 3/8 complex with a monoclonal antibody in patients with mixed hyperlipidemia: a phase 1 trial.Nature medicine · 2025Trial
- Effects of fenofibrate on angiopoietin-like 3/4/8 proteins and apolipoprotein A5.Journal of lipid research · 2026Article
- Associations of ANGPTL3/4/8 proteins and complexes with heart failure and heart failure mortality.Lipids in health and disease · 2026Article
- Unraveling the physiological impact of ANGPTL8 loss-of-function variants in humans.Scientific reports · 2026Article
- Investigation of the relationship between carotid intima-media thickness and angiopoietin-like factor 3 levels in metabolic dysfunction-associated steatotic liver disease.Scientific reports · 2026Article
- A neutralizing APOA5 monoclonal antibody reduces amounts of lipoprotein lipase in capillaries and triggers hypertriglyceridemia.Proceedings of the National Academy of Sciences of the United States of America · 2026Article
- Molecular characterization of a rare heterozygousFrontiers in genetics · 2026Article
- Time-Restricted Eating, ANGPTL4, and Reduction in Residual Cardiovascular Risk.Journal of clinical medicine · 2025Article
- ANGPTL3: A Breakthrough Target in Treatment for Dyslipidemia and Atherosclerosis.Journal of atherosclerosis and thrombosis · 2025Review
- ANGPTL3/8 is an atypical unfoldase that regulates intravascular lipolysis by catalyzing unfolding of lipoprotein lipase.Proceedings of the National Academy of Sciences of the United States of America · 2025Article
- Treatment With Evinacumab Links a New Pathogenic Variant in the LPL Gene to Persistent Chylomicronemia.Journal of the Endocrine Society · 2025Article
- Review
- Antibody-Based Therapeutics for Hypercholesterolemia.Biologics : targets & therapy · 2025Review
- Inhibition of the ANGPTL3/8 Complex for the Prevention and Treatment of Atherosclerotic Cardiovascular Disease.Current atherosclerosis reports · 2024Review
- Angiopoietin-like Proteins and Lipoprotein Lipase: The Waltz Partners That Govern Triglyceride-Rich Lipoprotein Metabolism? Impact on Atherogenesis, Dietary Interventions, and Emerging Therapies.Journal of clinical medicine · 2024Article
- Postprandial exercise regulates tissue-specific triglyceride uptake through angiopoietin-like proteins.JCI insight · 2024Article
- APOA5 deficiency causes hypertriglyceridemia by reducing amounts of lipoprotein lipase in capillaries.Journal of lipid research · 2024Review
- A unified model for regulating lipoprotein lipase activity.Trends in endocrinology and metabolism: TEM · 2024Review
- Carboxyl-terminal sequences in APOA5 are important for suppressing ANGPTL3/8 activity.Proceedings of the National Academy of Sciences of the United States of America · 2024Article
Corrections and comments
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Authors and funding
17 authors at 1 institution in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
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.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.