{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,16]],"date-time":"2026-04-16T17:14:52Z","timestamp":1776359692090,"version":"3.51.2"},"reference-count":47,"publisher":"Wiley","issue":"11","license":[{"start":{"date-parts":[[2020,10,28]],"date-time":"2020-10-28T00:00:00Z","timestamp":1603843200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Liver International"],"published-print":{"date-parts":[[2020,11]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Background &amp; Aims<\/jats:title>\n                    <jats:p>While fibrosis stage predicts liver\u2010associated mortality, cardiovascular disease (CVD) is still the major overall cause of mortality in patients with NASH. Novel NASH drugs should thus ideally reduce both liver fibrosis and CVD. Icosabutate is a semi\u2010synthetic, liver\u2010targeted eicosapentaenoic acid (EPA) derivative in clinical development for NASH. The primary aims of the current studies were to establish both the anti\u2010fibrotic and anti\u2010atherogenic efficacy of icosabutate in conjunction with changes in lipotoxic and atherogenic lipids in liver and plasma respectively.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      The effects of icosabutate on fibrosis progression and lipotoxicity were investigated in amylin liver NASH (AMLN) diet (high fat, cholesterol and fructose) fed\n                      <jats:italic>ob\/ob<\/jats:italic>\n                      mice with biopsy\u2010confirmed steatohepatitis and fibrosis and compared with the activity of obeticholic acid. APOE*3Leiden.CETP mice, a translational model for hyperlipidaemia and atherosclerosis, were used to evaluate the mechanisms underlying the lipid\u2010lowering effect of icosabutate and its effect on atherosclerosis.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      In AMLN\n                      <jats:italic>ob\/ob<\/jats:italic>\n                      mice, icosabutate significantly reduced hepatic fibrosis and myofibroblast content in association with downregulation of the arachidonic acid cascade and a reduction in both hepatic oxidised phospholipids and apoptosis. In APOE*3Leiden.CETP mice, icosabutate reduced plasma cholesterol and TAG levels via increased hepatic uptake, upregulated hepatic lipid metabolism and downregulated inflammation pathways, and effectively decreased atherosclerosis development.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>Icosabutate, a structurally engineered EPA derivative, effectively attenuates both hepatic fibrosis and atherogenesis and offers an attractive therapeutic approach to both liver\u2010 and CV\u2010related morbidity and mortality in NASH patients.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1111\/liv.14643","type":"journal-article","created":{"date-parts":[[2020,8,26]],"date-time":"2020-08-26T03:48:20Z","timestamp":1598413700000},"page":"2860-2876","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":15,"title":["Dual targeting of hepatic fibrosis and atherogenesis by icosabutate, an engineered eicosapentaenoic acid derivative"],"prefix":"10.1111","volume":"40","author":[{"given":"Geurt","family":"Stokman","sequence":"first","affiliation":[{"name":"TNO Metabolic Health Research Leiden The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Anita M.","family":"van den Hoek","sequence":"additional","affiliation":[{"name":"TNO Metabolic Health Research Leiden The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ditte","family":"Denker Thorbekk","sequence":"additional","affiliation":[{"name":"Gubra H\u00f8rsholm Denmark"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Elsbet J.","family":"Pieterman","sequence":"additional","affiliation":[{"name":"TNO Metabolic Health Research Leiden The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sanne","family":"Skovg\u00e5rd Veidal","sequence":"additional","affiliation":[{"name":"Gubra H\u00f8rsholm Denmark"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Brittany","family":"Basta","sequence":"additional","affiliation":[{"name":"Division of Liver Diseases Icahn School of Medicine at Mount Sinai New York NY USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Marta","family":"Iruarrizaga\u2010Lejarreta","sequence":"additional","affiliation":[{"name":"OWL Metabolomics Parque Tecnol\u00f3gico de Bizkaia Zamudio Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jos\u00e9 W.","family":"van der Hoorn","sequence":"additional","affiliation":[{"name":"TNO Metabolic Health Research Leiden The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Lars","family":"Verschuren","sequence":"additional","affiliation":[{"name":"TNO Microbiology &amp; Systems Biology Zeist The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jimmy F. P.","family":"Berb\u00e9e","sequence":"additional","affiliation":[{"name":"Department. of Medicine Division of Endocrinology Einthoven Laboratory for Experimental Vascular Medicine Leiden University Medical Center Leiden The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Patrick C. N.","family":"Rensen","sequence":"additional","affiliation":[{"name":"Department. of Medicine Division of Endocrinology Einthoven Laboratory for Experimental Vascular Medicine Leiden University Medical Center Leiden The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Tore","family":"Skj\u00e6ret","sequence":"additional","affiliation":[{"name":"NorthSea Therapeutics BV Amsterdam The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Cristina","family":"Alonso","sequence":"additional","affiliation":[{"name":"Division of Liver Diseases Icahn School of Medicine at Mount Sinai New York NY USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Michael","family":"Feigh","sequence":"additional","affiliation":[{"name":"Gubra H\u00f8rsholm Denmark"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"John J. 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