Background & 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 the translational potential of these findings, effects on elevated liver enzymes and fibrosis-4 (FIB-4) score were assessed in overweight, hyperlipidaemic patients at 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 dyslipidaemic patients at risk of NASH, icosabutate rapidly normalised elevated plasma ALT, GGT and AST and reduced FIB-4 in patients with elevated ALT and/or AST.

Conclusion

Icosabutate does not accumulate in hepatocytes and confers beneficial effects on hepatic oxidative stress, inflammation and fibrosis in mice. In conjunction with reductions in markers of liver injury in hyperlipidaemic patients, these findings suggest that structural engineering of LCn-3FAs offers a novel approach for the treatment of NASH.

Lay summary

Long-chain omega-3 fatty acids are involved in multiple pathways regulating hepatic inflammation and fibrosis, but their susceptibility to peroxidation and use as an energy source may limit their clinical efficacy. Herein, we show that a structurally modified omega-3 fatty acid, icosabutate, overcame these challenges and had markedly improved antifibrotic efficacy in a mouse model of non-alcoholic steatohepatitis. A hepatoprotective effect of icosabutate was also observed in patients with elevated circulating lipids, in whom it led to rapid reductions in markers of liver injury.

中文翻译：

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一种结构工程脂肪酸，二十碳酸酯，可抑制 NASH 中的肝脏炎症和纤维化

背景与目标

尽管长链 omega-3 脂肪酸 (LCn-3FAs) 调节与非酒精性脂肪性肝炎 (NASH) 相关的炎症通路，但它们对过氧化的敏感性可能会限制它们的治疗潜力。我们在体外比较了二十碳五烯酸 (EPA) 与工程化 EPA 衍生物 (二十碳丁酸酯) 在人肝细胞中的代谢，以及它们对 NASH 饮食小鼠模型和易患患者的肝谷胱甘肽代谢、氧化脂质、炎症和纤维化的影响对脂肪肝。

方法

在原代人肝细胞中比较了 EPA 和 icosabutate 的氧化率和细胞分配。将低剂量（56 毫克/千克）或高剂量（112 毫克/千克）二十烷酸延迟治疗与 EPA（91 毫克/千克）或胰高血糖素样肽 1 受体激动剂在胆碱缺乏症中的比较效果进行了比较(CD)，L-氨基酸定义的 NASH 小鼠模型。为了评估这些发现的转化潜力，在 NASH 风险增加的超重、高脂血症患者中评估了对升高的肝酶和纤维化 4 (FIB-4) 评分的影响。

结果

与 EPA 相比，icosabutate 抗氧化和掺入肝细胞。Icosabutate 还减少了炎症和纤维化，同时逆转了 CD 饮食引起的肝脂质组变化。EPA 对任何参数的影响都很小，甚至与肝谷胱甘肽耗竭相关的纤维化恶化。在有 NASH 风险的血脂异常患者中，icosabutate 迅速使升高的血浆 ALT、GGT 和 AST 正常化，并降低 ALT 和/或 AST 升高的患者的 FIB-4。

结论

Icosabutate 不会在肝细胞中积累，并且对小鼠的肝脏氧化应激、炎症和纤维化具有有益作用。结合高脂血症患者肝损伤标志物的减少，这些发现表明 LCn-3FAs 的结构工程为治疗 NASH 提供了一种新方法。

总结

长链 omega-3 脂肪酸参与调节肝脏炎症和纤维化的多种途径，但它们对过氧化的敏感性和用作能源可能会限制它们的临床疗效。在这里，我们展示了一种结构修饰的 omega-3 脂肪酸，即 icosabutate，克服了这些挑战，并在非酒精性脂肪性肝炎小鼠模型中显着提高了抗纤维化功效。在循环血脂升高的患者中也观察到了二十碳酸盐的保肝作用，在这些患者中，它导致肝损伤标志物的迅速减少。