Icosabutate Exerts Beneficial Effects Upon Insulin Sensitivity, Hepatic Inflammation, Lipotoxicity, and Fibrosis in Mice

Abstract

Icosabutate is a structurally engineered eicosapentaenoic acid derivative under development for nonalcoholic steatohepatitis (NASH). In this study, we investigated the absorption and distribution properties of icosabutate in relation to liver targeting and used rodents to evaluate the effects of icosabutate on glucose metabolism, insulin resistance, as well as hepatic steatosis, inflammation, lipotoxicity, and fibrosis. The absorption, tissue distribution, and excretion of icosabutate was investigated in rats along with its effects in mouse models of insulin resistance ( ob/ob) and metabolic inflammation/NASH (high‐fat/cholesterol‐fed APOE*3Leiden.CETP mice) and efficacy was compared with synthetic peroxisome proliferator‐activated receptor α (PPAR‐α) (fenofibrate) and/or PPAR‐γ/(α) (pioglitazone and rosiglitazone) agonists. Icosabutate was absorbed almost entirely through the portal vein, resulting in rapid hepatic accumulation. Icosabutate demonstrated potent insulin‐sensitizing effects in ob/ob mice, and unlike fenofibrate or pioglitazone, it significantly reduced plasma alanine aminotransferase. In high‐fat/cholesterol‐fed APOE*3Leiden.CETP mice, icosabutate, but not rosiglitazone, reduced microvesicular steatosis and hepatocellular hypertrophy. Although both rosiglitazone and icosabutate reduced hepatic inflammation, only icosabutate elicited antifibrotic effects in association with decreased hepatic concentrations of multiple lipotoxic lipid species and an oxidative stress marker. Hepatic gene‐expression analysis confirmed the changes in lipid metabolism, inflammatory and fibrogenic response, and energy metabolism, and revealed the involved upstream regulators. In conclusion, icosabutate selectively targets the liver through the portal vein and demonstrates broad beneficial effects following insulin sensitivity, hepatic microvesicular steatosis, inflammation, lipotoxicity, oxidative stress, and fibrosis. Icosabutate therefore offers a promising approach to the treatment of both dysregulated glucose/lipid metabolism and inflammatory disorders of the liver, including NASH.

Abstract

The aim of the present study was to evaluate the effects of icosabutate, a structurally engineered eicosapentaenoic acid (EPA) derivative, designed to overcome the inherent drawbacks of unmodified EPA for liver targeting. As a multi‐etiological disorder with limited success achieved to date with single target drugs, nonalcoholic steatohepatitis (NASH) is an attractive indication for drugs with pleiotropic targeting potential, such as ω‐3 fatty acids. However, a potentially important issue limiting their clinical efficacy is related to suboptimal liver targeting of ω‐3 fatty acids, which could be rectified through structural engineering. In this study, we investigated icosabutate in relation to liver targeting and used rodent models to evaluate the effects of icosabutate on glucose metabolism, insulin resistance, as well as NASH and fibrosis.