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.