Multi‐omic network analysis identified betacellulin as a novel target of omega‐3 fatty acid attenuation of western diet‐induced nonalcoholic steatohepatitis

Clinical and preclinical studies have established that supplementing diets with ω3 polyunsaturated fatty acids (PUFA) can reduce hepatic dysfunction in nonalcoholic steatohepatitis (NASH). Herein, we used multi-omic network analysis to unveil novel mechanistic targets of ω3 PUFA effects in a preclinical mouse model of western diet induced NASH. After identifying critical molecular processes responsible for the effects of ω3 PUFA, we next performed meta-analysis of human liver cancer transcriptomes and uncovered betacellulin as a key EGFR-binding protein that was induced in liver cancer and downregulated by ω3 PUFAs in animals with NASH. We then confirmed that betacellulin acts by promoting proliferation of quiescent hepatic stellate cells, stimulating 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 antifibrotic effects of ω3 PUFA during NASH. Synopsis Multi-omic network analysis points to mitochondrial cardiolipin precursors as candidate key lipids whereby ω3 fatty acids restore mitochondrial functioning. Multi-omic network analysis suggests betacellulin (BTC) as one of the key mediators of NASH suppressed by ω3 polyunsaturated fatty acids. Reduction of liver fibrosis by omega-3 fatty acids (especially by docosahexaenoic acid, DHA) is accomplished by simultaneous inhibition of betacellulin and TLR agonists. BTC promotes collagen production and induces TGFB2 in hepatic stellate cells. BTC together with TLR2/4 agonists stimulate expression of integrins in macrophages. DHA suppresses BTC-EGFR pathway in NASH animal model potentially preventing progression to hepatocellular carcinoma.

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