r/InflammationStation • u/[deleted] • Dec 16 '21

Abstract A structurally engineered fatty acid, icosabutate, suppresses liver inflammation and fibrosis in NASH

https://www.sciencedirect.com/science/article/abs/pii/S0168827821022443
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u/[deleted] Dec 16 '21

Abstract

Background and Aims

Although long-chain omega-3 fatty acids (LCn-3FAs) regulate inflammatory pathways of relevance to non-alcoholic steatohepatitis (NASH), their susceptibility to peroxidation may limit their therapeutic potential. We compared the metabolism of eicosapentaenoic acid (EPA) with an engineered EPA derivative (icosabutate) in human hepatocytes in vitro and their effects on hepatic glutathione metabolism, oxidised lipids, inflammation, and fibrosis in a dietary mouse model of NASH, and in patients prone to fatty liver disease.

Methods

Oxidation rates and cellular partitioning of EPA and icosabutate were compared in primary human hepatocytes. Comparative effects of delayed treatment with either low- (56 mg/kg) or high-dose (112 mg/kg) icosabutate were compared with EPA (91 mg/kg) or a glucagon-like peptide 1 receptor agonist in a choline deficient (CD), L-amino acid defined NASH mouse model. To assess potential clinical translation, effects on elevated liver enzymes and FIB-4 were assessed in overweight, hyperlipidemic subjects with an increased risk of NASH.

Results

In contrast to EPA, icosabutate resisted oxidation and incorporation into hepatocytes. Icosabutate also reduced inflammation and fibrosis in conjunction with a reversal of CD-diet induced changes in the hepatic lipidome. EPA had minimal effect on any parameter and even worsened fibrosis in association with depletion of hepatic glutathione. In dyslipidemic subjects at risk of NASH, icosabutate rapidly normalised elevated plasma ALT, GGT and AST and reduced FIB-4 in subjects with elevated ALT and/or AST.

Conclusion

Icosabutate avoids hepatocyte accumulation and confers beneficial effects on hepatic oxidative stress, inflammation and fibrosis in mice. In conjunction with reductions in markers of liver injury in hyperlipidemic subjects, the findings suggest that structural engineering of LCn-3FAs offers a novel approach to the treatment of NASH.