{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,6]],"date-time":"2026-10-06T12:16:52Z","timestamp":1791289012061,"version":"4.3.0"},"reference-count":51,"publisher":"Oxford University Press (OUP)","issue":"17","license":[{"start":{"date-parts":[[2024,9,11]],"date-time":"2024-09-11T00:00:00Z","timestamp":1726012800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100002996","name":"Dutch Heart Foundation","doi-asserted-by":"publisher","award":["2017T016"],"award-info":[{"award-number":["2017T016"]}],"id":[{"id":"10.13039\/501100002996","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100019657","name":"Netherlands Cardiovascular Research","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100019657","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100009708","name":"Novo Nordisk Foundation","doi-asserted-by":"publisher","award":["NNF18OC0032394"],"award-info":[{"award-number":["NNF18OC0032394"]}],"id":[{"id":"10.13039\/501100009708","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2024,12,31]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:sec>\n                  <jats:title>Aims<\/jats:title>\n                  <jats:p>Angiopoietin-like 3 (ANGPTL3) and 4 (ANGPTL4) inhibit lipoprotein lipase to regulate tissue fatty acid (FA) uptake from triglyceride (TG)-rich lipoproteins such as very low density lipoproteins (VLDL). While pharmacological inhibition of ANGPTL3 is being evaluated as a lipid-lowering strategy, systemic ANGPTL4 inhibition is not pursued due to adverse effects. This study aims to compare the therapeutic potential of liver-specific Angptl3 and Angptl4 silencing to attenuate hyperlipidemia and atherosclerosis development in APOE*3-Leiden.CETP mice, a well-established humanized model for lipoprotein metabolism.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Methods and results<\/jats:title>\n                  <jats:p>Mice were subcutaneously injected twice per week with saline or liver-targeted antisense oligonucleotides against Angptl3, Angptl4, both, or a scrambled oligonucleotide. Plasma lipid levels, VLDL clearance, and hepatic VLDL production were determined, and atherosclerosis development was assessed. For toxicological evaluation, cynomolgus monkeys were treated with three dosages of liver-targeted ANGPTL4-silencing oligonucleotides. Liver-targeted Angptl4 silencing reduced plasma TGs (\u221248%) and total cholesterol (\u221256%), explained by higher VLDL-derived FA uptake by brown adipose tissue and lower VLDL production by the liver. Accordingly, Angptl4 silencing reduced atherosclerotic lesion size (\u221286%) and improved lesion stability. Hepatic Angptl3 silencing similarly attenuated hyperlipidemia and atherosclerosis development. While Angptl3 and Angptl4 silencing lowered plasma TGs in the refed and fasted state, respectively, combined Angptl3\/4 silencing lowered plasma TGs independent of the nutritional state. In cynomolgus monkeys, anti-ANGPTL4 ASO treatment was well tolerated without adverse effects.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Conclusion<\/jats:title>\n                  <jats:p>Liver-targeted Angptl4 silencing potently attenuates hyperlipidemia and atherosclerosis development in APOE*3-Leiden.CETP mice, and liver-targeted ANGPTL4 silencing is well tolerated in non-human primates. These data warrant further clinical development of liver-targeted ANGPTL4 silencing.<\/jats:p>\n               <\/jats:sec>","DOI":"10.1093\/cvr\/cvae195","type":"journal-article","created":{"date-parts":[[2024,9,11]],"date-time":"2024-09-11T23:06:47Z","timestamp":1726096007000},"page":"2179-2190","source":"Crossref","is-referenced-by-count":18,"title":["Liver-targeted <i>Angptl4<\/i> silencing by antisense oligonucleotide treatment attenuates hyperlipidaemia and atherosclerosis development in APOE*3-Leiden.CETP mice"],"prefix":"10.1093","volume":"120","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-8715-1586","authenticated-orcid":false,"given":"Melanie","family":"Modder","sequence":"first","affiliation":[{"name":"Division of Endocrinology, Department of Medicine, Leiden University Medical Center , Albinusdreef 2, 2333 ZA Leiden ,","place":["The Netherlands"]},{"name":"Einthoven Laboratory for Experimental Vascular Medicine, Leiden University Medical Center , Albinusdreef 2, 2333 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,","place":["The Netherlands"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Salwa","family":"Afkir","sequence":"additional","affiliation":[{"name":"Division of Endocrinology, Department of Medicine, Leiden University Medical Center , Albinusdreef 2, 2333 ZA Leiden ,","place":["The Netherlands"]},{"name":"Einthoven Laboratory for Experimental Vascular Medicine, Leiden University Medical Center , Albinusdreef 2, 2333 ZA Leiden ,","place":["The Netherlands"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alexandra L","family":"Dorn","sequence":"additional","affiliation":[{"name":"Division of Endocrinology, Department of Medicine, Leiden University Medical Center , Albinusdreef 2, 2333 ZA Leiden ,","place":["The Netherlands"]},{"name":"Einthoven Laboratory for Experimental Vascular Medicine, Leiden University Medical Center , Albinusdreef 2, 2333 ZA Leiden ,","place":["The 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