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

Abstract

Nonalcoholic steatohepatitis (NASH) is currently the only prevalent metabolic disease with no FDA-approved treatment strategy. Supplementation of omega-3 polyunsaturated fatty acids (PUFA) represent a promising treatment as it can attenuate fibrosis and inflammation, but the mechanisms are poorly defined. We employed a causal inference approach for multi-omics network analysis which revealed critical cellular and molecular processes responsible for the effects of omega-3 PUFA (Docosahexaenoic acid, DHA; Eicosapentaenoic acid, EPA) in a preclinical mouse model of NASH. Because NASH is one of the leading causes of liver cancer, we also performed a meta-analysis of 7 cancer datasets and integrated these results with the mouse gene expression network. The overlap of the NASH network with meta-analysis identified betacellulin (BTC)-EGFR-ERBB as a central pathway of hepatocellular carcinoma. In mice, DHA inhibits this pathway. Using two cell lines, we confirmed that BTC acts at several levels of pathogenesis by: 1) promoting proliferation of quiescent hepatic stellate cells; 2) stimulating transforming growth factor-beta 2 (TGFB-2), which increases collagen production, and 3) upregulation of integrins in macrophages together with TLR2/4 agonists. Strikingly, these pathogenic processes were attenuated by DHA and to a much lesser degree by EPA. We also found that DHA restores hepatic cardiolipin precursors and mitochondrial pathways. Together, our results suggest that inhibition of BTC by DHA is a key mechanism behind its beneficial effects on liver health, and that administration of DHA may prevent progression of NASH to liver cancer by averting the BTC-EGFR-ERBB pathway.

Machine learning reveals the interplay between muscle fatty acids and the gut microbiota: implications for high-quality pork

“…Indeed, a greater abundance of gut Dorea accompanied by increased serum C18:1n9c levels had an anti-in ammatory effect in an animal model of ulcerative colitis [43]. An obeselinked fatty acid pro le was characterized by a decrease in functional fatty acids [33], and increasing the intake of PUFAs, especially GLA, DHA, and EPA, is also recommended because of the decreased incidence of cardiovascular and metabolic diseases [8, [44][45][46][47]. Thus, foods rich in these functional fatty acids, such as meat, nuts, and edible oils, have attracted much attention due to their metabolic bene ts.…”

Early transcriptome changes associated with western diet induced NASH in Ldlr−/− mice points to activation of hepatic macrophages and an acute phase response

“…Briefly, the normalized unique molecular identifier or UMI > 1.0, with a significant fold change and uniquely expressed genes in a cell specific cluster were then assigned to that specific set of genes in the time course bulk RNASeq data to indicate they belong to that specific cell type ( 30 ).…”