Omega-3 polyunsaturated fatty acids reduce hepatic dysfunction in nonalcoholic steatohepatitis (NASH) by lowering betacellulin (BTC), a protein growth factor that contributes to liver fibrosis and progression to cirrhosis and liver cancer, new data suggest.
Because omega-3 polyunsaturated fatty acids have been shown to reduce hepatic dysfunction in NASH, but the molecular underpinnings of this action were elusive, researchers conducted a multiomic network analysis applied to a mouse model of Western diet–induced NASH to identify the key mechanisms involved.
They also performed a meta-analysis of human liver cancer transcriptome data to evaluate which aspects of NASH pathogenesis leading to cancer are reversed by omega-3 polyunsaturated fatty acids.
BTC, an epidermal growth factor–binding protein, was consistently upregulated in liver cancer and downregulated by omega-3 polyunsaturated fatty acids in mice and humans with NASH.
BTC promotes NASH fibrosis by activating dormant hepatic stellate cells to produce transforming growth factor beta-2 and increase collagen production. It also exacerbates toll-like receptor-dependent inflammatory processes in NASH.
By downregulating BTC, omega-3 polyunsaturated fatty acids have therapeutic potential in NASH and could serve as a novel drug target.
“BTC represents a candidate master regulator inducing two most important factors (collagens and integrins) contributing to liver fibrosis and consequently promoting liver cancer,” the researchers write. “Future studies should investigate if BTC-triggered gene expression signatures can serve as biomarkers guiding personalized [omega-3 polyunsaturated fatty acid] therapy, as targets of new NAFLD/NASH drugs, and finally as a predictors of hepatic cancer risk in humans.”
The study, with lead first author Jyothi Padiadpu, PhD, Oregon State University College of Pharmacy in Corvallis, was published online October 20 in EMBO Molecular Medicine.
The study authors report no limitations. However, the findings are based on mouse model and human transcriptome data.
This research was supported by the National Institute of Diabetes and Digestive Kidney Diseases and the US Department of Agriculture. The authors report no conflicts of interest.
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Publish date : 2023-11-14 13:55:05
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