Title
Dual targeting of hepatic fibrosis and atherogenesis by icosabutate, an engineered eicosapentaenoic acid derivative
Author
Stokman, G.
van den Hoek, A.M.
Denker Thorbekk, D.
Pieterman, E.J.
Skovgård Veidal, S.
Basta, B.
Iruarrizaga-Lejarreta, M.
van der Hoorn, J.W.
Verschuren, L.
Berbée, J.F.P.
Rensen, P.C.N.
Skjæret, T.
Alonso, C.
Feigh, M.
Kastelein, J.J.P.
Friedman, S.L.
Princen, H.M.G.
Fraser, D.A.
Publication year
2020
Subject
Apoptosis
Arachidonic acid
Atherosclerosis
Lipotoxicity
NASH
Oxidised phospholipids
Biomedical Innovation
Healthy Living
Life
MHR - Metabolic Health Research
ELSS - Earth, Life and Social Sciences
To reference this document use:
http://resolver.tudelft.nl/uuid:919fdf9a-63dd-46d9-ab0a-31057d79e3e9
DOI
https://doi.org/10.1111/liv.14643
TNO identifier
882395
Source
Liver International, 40 (40), 2860-2876
Bibliographical note
Background & Aims: While fibrosis stage predicts liver-associated 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-synthetic, liver-targeted eicosapentaenoic acid (EPA) derivative in clinical development for NASH. The primary aims of the current studies were to establish both the anti-fibrotic and anti-atherogenic efficacy of icosabutate in conjunction with changes in lipotoxic and atherogenic lipids in liver and plasma respectively. Methods: The effects of icosabutate on fibrosis progression and lipotoxicity were investigated in amylin liver NASH (AMLN) diet (high fat, cholesterol and fructose) fed ob/ob mice with biopsy-confirmed 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-lowering effect of icosabutate and its effect on atherosclerosis. Results: In AMLN ob/ob 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. Conclusions: Icosabutate, a structurally engineered EPA derivative, effectively attenuates both hepatic fibrosis and atherogenesis and offers an attractive therapeutic approach to both liver- and CV-related morbidity and mortality in NASH patients. © 2020 The Authors. Liver International published by John Wiley & Sons Ltd
Document type
article