Clinical and preclinical studies established that supplementing diets with ω3 polyunsaturated fatty acids (PUFA) can reduce hepatic dysfunction in nonalcoholic steatohepatitis (NASH) but molecular underpinnings of this action were elusive. Herein, we used multi-omic network analysis that unveiled critical molecular pathways involved in ω3 PUFA effects in a preclinical mouse model of western diet induced NASH. Since NASH is a precursor of liver cancer, we also performed meta-analysis of human liver cancer transcriptomes that uncovered betacellulin as a key EGFR-binding protein upregulated in liver cancer and downregulated by ω3 PUFAs in animals and humans with NASH. We then confirmed that betacellulin acts by promoting proliferation of quiescent hepatic stellate cells, inducing transforming growth factor–β2 and increasing collagen production. When used in combination with TLR2/4 agonists, betacellulin upregulated integrins in macrophages thereby potentiating inflammation and fibrosis. Taken together, our results suggest that suppression of betacellulin is one of the key mechanisms associated with anti-inflammatory and anti-fibrotic effects of ω3 PUFA on NASH.

中文翻译：

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多组学网络分析确定 betacellulin 是西方饮食诱导的非酒精性脂肪性肝炎 omega-3 脂肪酸减弱的新靶点

临床和临床前研究证实，在饮食中补充 ω3 多不饱和脂肪酸 (PUFA) 可以减少非酒精性脂肪性肝炎 (NASH) 的肝功能障碍，但这种作用的分子基础尚不清楚。在此，我们使用多组学网络分析揭示了在西方饮食诱导 NASH 的临床前小鼠模型中涉及 ω3 PUFA 效应的关键分子途径。由于 NASH 是肝癌的前兆，我们还对人类肝癌转录组进行了荟萃分析，发现 betacellulin 作为一种关键的 EGFR 结合蛋白，在肝癌中上调，并在患有 NASH 的动物和人类中被 ω3 PUFA 下调。然后我们证实，βcellulin 通过促进静止肝星状细胞增殖、诱导转化生长因子-β2 和增加胶原蛋白产生来发挥作用。当与 TLR2/4 激动剂联合使用时，βcellulin 上调巨噬细胞中的整合素，从而加剧炎症和纤维化。综上所述，我们的结果表明，β细胞素的抑制是与 ω3 PUFA 对 NASH 的抗炎和抗纤维化作用相关的关键机制之一。