TitleMulti-omic network analysis identified betacellulin as a novel target of omega-3 fatty acid attenuation of western diet-induced nonalcoholic steatohepatitis.
Publication TypeJournal Article
Year of Publication2023
AuthorsPadiadpu J, Garcia-Jaramillo M, Newman NK, Pederson JW, Rodrigues R, Li Z, Singh S, Monnier P, Trinchieri G, Brown K, Dzutsev AK, Shulzhenko N, Jump DB, Morgun A
JournalEMBO Mol Med
Date Published2023 Nov 08
KeywordsAnimals, Betacellulin, Diet, Western, Disease Models, Animal, Fatty Acids, Omega-3, Fibrosis, Humans, Liver, Liver Neoplasms, Mice, Mice, Inbred C57BL, Multiomics, Non-alcoholic Fatty Liver Disease

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.

Alternate JournalEMBO Mol Med
PubMed ID37859621
PubMed Central IDPMC10630881
Grant ListR01 DK094600 / DK / NIDDK NIH HHS / United States
R01 DK103761 / DK / NIDDK NIH HHS / United States
R01 DK112360 / DK / NIDDK NIH HHS / United States