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Herein, we used multi\u2010omic network analysis that unveiled critical molecular pathways involved in \u03c93 PUFA effects in a preclinical mouse model of western diet induced NASH. Since NASH is a precursor of liver cancer, we also performed meta\u2010analysis of human liver cancer transcriptomes that uncovered betacellulin as a key EGFR\u2010binding protein upregulated in liver cancer and downregulated by \u03c93 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\u2013\u03b22 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\u2010inflammatory and anti\u2010fibrotic effects of \u03c93 PUFA on NASH.<\/jats:p>","DOI":"10.15252\/emmm.202318367","type":"journal-article","created":{"date-parts":[[2023,10,20]],"date-time":"2023-10-20T04:11:18Z","timestamp":1697775078000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":12,"title":["Multi\u2010omic network analysis identified betacellulin\u00a0as a novel target of omega\u20103 fatty acid\u00a0attenuation of western diet\u2010induced nonalcoholic steatohepatitis"],"prefix":"10.1038","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-9507-6133","authenticated-orcid":false,"given":"Jyothi","family":"Padiadpu","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2987-2913","authenticated-orcid":false,"given":"Manuel","family":"Garcia\u2010Jaramillo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nolan K","family":"Newman","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jacob W","family":"Pederson","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Richard","family":"Rodrigues","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhipeng","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0004-0751-6541","authenticated-orcid":false,"given":"Sehajvir","family":"Singh","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Philip","family":"Monnier","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Giorgio","family":"Trinchieri","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kevin","family":"Brown","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0749-4149","authenticated-orcid":false,"given":"Amiran K","family":"Dzutsev","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0077-8456","authenticated-orcid":false,"given":"Natalia","family":"Shulzhenko","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9473-6283","authenticated-orcid":false,"given":"Donald B","family":"Jump","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8924-6108","authenticated-orcid":false,"given":"Andrey","family":"Morgun","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2023,10,20]]},"reference":[{"key":"BFEMMM202318367_CR1","doi-asserted-by":"crossref","first-page":"D892","DOI":"10.1093\/nar\/gkaa1054","volume":"49","author":"I Abugessaisa","year":"2021","unstructured":"Abugessaisa I, Ramilowski JA, Lizio M, Severin J, Hasegawa A, Harshbarger J, Kondo A, Noguchi S, Yip CW, Ooi JLC et\u00a0al (2021) FANTOM enters 20th year: expansion of transcriptomic atlases and functional annotation of non\u2010coding RNAs. 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