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Title: Fructose stimulated de novo lipogenesis is promoted by inflammation.

Authors: Todoric, Jelena; Di Caro, Giuseppe; Reibe, Saskia; Henstridge, Darren C; Green, Courtney R; Vrbanac, Alison; Ceteci, Fatih; Conche, Claire; McNulty, Reginald; Shalapour, Shabnam; Taniguchi, Koji; Meikle, Peter J; Watrous, Jeramie D; Moranchel, Rafael; Najhawan, Mahan; Jain, Mohit; Liu, Xiao; Kisseleva, Tatiana; Diaz-Meco, Maria T; Moscat, Jorge; Knight, Rob; Greten, Florian R; Lau, Lester F; Metallo, Christian M; Febbraio, Mark A; Karin, Michael

Published In Nat Metab, (2020 10)

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.

PubMed ID: 32839596 Exiting the NIEHS site

MeSH Terms: Acetyl Coenzyme A/pharmacology; Animals; Endotoxemia/blood; Female; Fructose/pharmacology*; Fructosephosphates/pharmacology; Gastrointestinal Microbiome; Hepatocytes/drug effects; Hepatocytes/metabolism; Humans; Inflammation/metabolism*; Intestines/drug effects; Lipidomics; Lipogenesis/drug effects*; Macrophages/metabolism; Mice; Mice, Inbred C57BL; Non-alcoholic Fatty Liver Disease/metabolism; Regeneration/drug effects; Toll-Like Receptors/agonists

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