Multi-omic network analysis identified betacellulin as a novel target of omega-3 fatty acid attenuation of western diet-induced nonalcoholic steatohepatitis.
Multi-omic network analysis identified betacellulin as a novel target of omega-3 fatty acid attenuation of western diet-induced nonalcoholic steatohepatitis.
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DOI：
10.15252/emmm.202318367
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发表时间：
2023-11-08
影响因子：
11.1
通讯作者：
Morgun, Andrey
中科院分区：
文献类型：
--
作者：
Padiadpu, Jyothi;Garcia-Jaramillo, Manuel;Newman, Nolan K.;Pederson, Jacob W.;Rodrigues, Richard;Li, Zhipeng;Singh, Sehajvir;Monnier, Philip;Trinchieri, Giorgio;Brown, Kevin;Dzutsev, Amiran K.;Shulzhenko, Natalia;Jump, Donald B.;Morgun, Andrey
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）可以减轻非酒精性脂肪性肝炎（NASH）患者的肝功能障碍，但这种作用的分子基础尚不明确。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作用的关键分子途径。由于NASH是肝癌的前体，我们还对人类肝癌转录组进行了meta分析，发现β细胞蛋白是一种关键的EGFR结合蛋白，在NASH动物和人类中，β细胞蛋白在肝癌中上调，而ω3 PUFAs下调。我们随后证实，β细胞素通过促进静止的肝星状细胞增殖，诱导转化生长因子-β2和增加胶原蛋白的产生而起作用。当与TLR2/4激动剂联合使用时，β细胞素上调巨噬细胞中的整合素，从而增强炎症和纤维化。综上所述，我们的研究结果表明，β细胞蛋白的抑制是ω3 PUFA对NASH抗炎和抗纤维化作用的关键机制之一。本研究采用系统方法，包括网络建模和实验验证，揭示了ω3多不饱和脂肪酸（PUFA）在NASH和肝癌中的作用新机制。结果表明，PUFA可抑制β细胞素，从而减轻肝纤维化和炎症。
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. This study employed a systems approach, involving network modeling and experimental validations, to uncover a new mechanism of action of ω3 polyunsaturated fatty acids (PUFA) in both NASH and liver cancer. It showed that PUFA inhibits betacellulin thereby decreasing liver fibrosis and inflammation.
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影响因子：
3.9
作者：
Fridén M;Rosqvist F;Ahlström H;Niessen HG;Schultheis C;Hockings P;Hulthe J;Gummesson A;Wanders A;Rorsman F;Risérus U;Vessby J
通讯作者：
Vessby J
影响因子：
14.9
作者：
Abugessaisa I;Ramilowski JA;Lizio M;Severin J;Hasegawa A;Harshbarger J;Kondo A;Noguchi S;Yip CW;Ooi JLC;Tagami M;Hori F;Agrawal S;Hon CC;Cardon M;Ikeda S;Ono H;Bono H;Kato M;Hashimoto K;Bonetti A;Kato M;Kobayashi N;Shin J;de Hoon M;Hayashizaki Y;Carninci P;Kawaji H;Kasukawa T
通讯作者：
Kasukawa T
βcellulin 对肺癌细胞产生 CXCL8 的调节机制
影响因子：
7.4
作者：
Shi L;Wang L;Wang B;Cretoiu SM;Wang Q;Wang X;Chen C
通讯作者：
Chen C
影响因子：
3.7
作者：
Depner CM;Traber MG;Bobe G;Kensicki E;Bohren KM;Milne G;Jump DB
通讯作者：
Jump DB
影响因子：
24.5
作者：
Dufour, Jean-Francois;Anstee, Quentin M.;Bugianesi, Elisabetta;Harrison, Stephen;Loomba, Rohit;Paradis, Valerie;Tilg, Herbert;Wong, Vincent Wai-Sun;Zelber-sagi, Shira
通讯作者：
Zelber-sagi, Shira