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Dual targeting of hepatic fibrosis and atherogenesis by icosabutate, an engineered eicosapentaenoic acid derivative
Author(s) -
Stokman Geurt,
Hoek Anita M.,
Denker Thorbekk Ditte,
Pieterman Elsbet J.,
Skovgård Veidal Sanne,
Basta Brittany,
IruarrizagaLejarreta Marta,
Hoorn José W.,
Verschuren Lars,
Berbée Jimmy F. P.,
Rensen Patrick C. N.,
Skjæret Tore,
Alonso Cristina,
Feigh Michael,
Kastelein John J. P.,
Friedman Scott L.,
Princen Hans M. G.,
Fraser David A.
Publication year - 2020
Publication title -
liver international
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.873
H-Index - 110
eISSN - 1478-3231
pISSN - 1478-3223
DOI - 10.1111/liv.14643
Subject(s) - fibrosis , medicine , hepatic fibrosis , lipotoxicity , eicosapentaenoic acid , endocrinology , hepatic stellate cell , nonalcoholic fatty liver disease , inflammation , fatty liver , polyunsaturated fatty acid , biology , insulin resistance , fatty acid , disease , insulin , biochemistry
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.