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bioRxiv · 10.1101/2022.10.03.510635

Suppression of Betacellulin expression is a key mechanism for omega-3 fatty acid mediated attenuation of nonalcoholic steatohepatitis

Padiadpu, J.·Garcia-Jaramillo, M.·Newman, N.·Pederson, J.·Rodrigues, R.·Li, Z.·Singh, S.·Monnier, P.·Trinchieri, G.·Brown, K.·Dzutsev, A. K.·Shulzhenko, N.·Jump, D. B.·Morgun, A.
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Abstract

Clinical and preclinical studies have established that supplementing diets with {omega}3 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 {omega}3 PUFA effects in a preclinical mouse model of western diet induced NASH. After identifying critical molecular processes responsible for the effects of {omega}3 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 {omega}3 PUFAs in animals with NASH. We then confirmed that betacellulin acts by promoting proliferation of quiescent hepatic stellate cells, stimulating transforming growth factor-{beta}2 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 {omega}3 PUFA during NASH. Synopsis O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=124 SRC="FIGDIR/small/510635v2_ufig1.gif" ALT="Figure 1"> View larger version (43K): org.highwire.dtl.DTLVardef@b8ebe7org.highwire.dtl.DTLVardef@879e8dorg.highwire.dtl.DTLVardef@1ba56f3org.highwire.dtl.DTLVardef@a26c67_HPS_FORMAT_FIGEXP M_FIG C_FIG O_LIMulti-omic network analysis points to mitochondrial cardiolipin precursors as candidate key lipids whereby {omega}3 fatty acids restore mitochondrial functioning. C_LIO_LIMulti-omic network analysis suggests betacellulin (BTC) as one of the key mediators of NASH suppressed by {omega}3 polyunsaturated fatty acids. C_LIO_LIReduction of liver fibrosis by omega-3 fatty acids (especially by docosahexaenoic acid, DHA) is accomplished by simultaneous inhibition of betacellulin and TLR agonists. C_LIO_LIBTC promotes collagen production and induces TGFB2 in hepatic stellate cells. C_LIO_LIBTC together with TLR2/4 agonists stimulate expression of integrins in macrophages. C_LIO_LIDHA suppresses BTC-EGFR pathway in NASH animal model potentially preventing progression to hepatocellular carcinoma. C_LI

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Padiadpu, J., Garcia-Jaramillo, M., Newman, N., Pederson, J., Rodrigues, R., Li, Z., Singh, S., Monnier, P., Trinchieri, G., Brown, K., Dzutsev, A. K., Shulzhenko, N., Jump, D. B., Morgun, A.. 2022-10-05. Suppression of Betacellulin expression is a key mechanism for omega-3 fatty acid mediated attenuation of nonalcoholic steatohepatitis. https://doi.org/10.1101/2022.10.03.510635

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