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Fructose stimulated de novo lipogenesis is promoted by inflammation


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Todoric, J, Di Caro, G, Reibe, S, Henstridge, DC ORCID: 0000-0003-4988-767X, Green, CR, Vrbanac, A, Ceteci, F, Conche, C, Shalapour, S, Taniguchi, K, McNulty, R, Meikle, P, Watrous, JD, Moranchel, R, Najhawan, M, Jain, M, Liu, X, Kisseleva, T, Diaz-Meco, MT, Moscat, J, Knight, R, Greten, FR, Lau, LF, Metallo, CM, Febbraio, MA and Karin, M 2020 , 'Fructose stimulated de novo lipogenesis is promoted by inflammation' , Nature Metabolism , doi: 10.1038/s42255-020-0261-2.

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Benign hepatosteatosis, affected by lipid uptake, de novo lipogenesis and fatty acid (FA) oxidation, progresses to non-alcoholic steatohepatitis (NASH) on stress and inflammation. A key macronutrient proposed to increase hepatosteatosis and NASH risk is fructose. Excessive intake of fructose causes intestinal-barrier deterioration and endotoxaemia. However, how fructose triggers these alterations and their roles in hepatosteatosis and NASH pathogenesis remain unknown. Here we show, using mice, that microbiota-derived Toll-like receptor (TLR) agonists promote hepatosteatosis without affecting fructose-1-phosphate (F1P) and cytosolic acetyl-CoA. Activation of mucosal-regenerative gp130 signalling, administration of the YAP-induced matricellular protein CCN1 or expression of the antimicrobial peptide Reg3b (beta) peptide counteract fructose-induced barrier deterioration, which depends on endoplasmic-reticulum stress and subsequent endotoxaemia. Endotoxin engages TLR4 to trigger TNF production by liver macrophages, thereby inducing lipogenic enzymes that convert F1P and acetyl-CoA to FA in both mouse and human hepatocytes.

Item Type: Article
Authors/Creators:Todoric, J and Di Caro, G and Reibe, S and Henstridge, DC and Green, CR and Vrbanac, A and Ceteci, F and Conche, C and Shalapour, S and Taniguchi, K and McNulty, R and Meikle, P and Watrous, JD and Moranchel, R and Najhawan, M and Jain, M and Liu, X and Kisseleva, T and Diaz-Meco, MT and Moscat, J and Knight, R and Greten, FR and Lau, LF and Metallo, CM and Febbraio, MA and Karin, M
Keywords: immunometabolism, liver, diabetes, cancer, gut, inflammation
Journal or Publication Title: Nature Metabolism
Publisher: Nature Publishing Group
ISSN: 2522-5812
DOI / ID Number: 10.1038/s42255-020-0261-2
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© 2020 Springer Nature. Post-prints are subject to Springer Nature re-use terms

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