Dual targeting of hepatic fibrosis and atherogenesis by icosabutate, an engineered eicosapentaenoic acid derivative.

Abstract

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.

• Authors: Geurt Stokman, Anita M van den Hoek, Ditte Denker Thorbekk, Elsbet J Pieterman, Sanne Skovgård Veidal, Brittany Basta, Marta Iruarrizaga-Lejarreta, José W van der Hoorn, Lars Verschuren, Jimmy F P Berbée, Patrick C N Rensen, Tore Skjaeret, Cristina Alonso, Michael Feigh, John J P Kastelein, Scott L Friedman, Hans M G Princen, David A Fraser
• Journal: Liver international : official journal of the International Association for the Study of the Liver (Liver Int) Vol. 40 Issue 11 Pg. 2860-2876 (11 2020) ISSN: 1478-3231 [Electronic] United States
• PMID: 32841505 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2020 The Authors. Liver International published by John Wiley & Sons Ltd.

Chemical References

• Butyrates
• icosabutate
• Eicosapentaenoic Acid

Topics

• Animals
• Atherosclerosis (drug therapy, pathology, prevention & control)
• Butyrates
• Disease Models, Animal
• Eicosapentaenoic Acid (pharmacology)
• Humans
• Liver (pathology)
• Liver Cirrhosis (drug therapy, pathology)
• Mice
• Mice, Inbred C57BL
• Non-alcoholic Fatty Liver Disease (drug therapy, pathology)