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Fructose stimulated de novo lipogenesis is promoted by inflammation
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Abstract
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 |
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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 |
Copyright Information: | © 2020 Springer Nature. Post-prints are subject to Springer Nature re-use terms |
Item Statistics: | View statistics for this item |
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