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

Abstract

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. image 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. Multi‐omic network of NASH and metanalysis of liver cancer pointed to betacellulin (BTC), a member of the epidermal growth factor family, as a key factor suppressed by ω3 PUFA, especially by docosahexaenoic acid (DHA). BTC induces collagen production, TGFB2 expression in hepatic stellate cells and combined with TLR2/4 agonists stimulates integrin expression in macrophages that altogether lead to fibrosis. DHA suppresses BTC‐EGFR pathway in NASH potentially preventing its progression to hepatocellular carcinoma. Mitochondrial cardiolipin precursors are candidate key lipids in improving mitochondrial functions by ω3 PUFA.