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Fructose stimulated de novo lipogenesis is promoted by inflammation


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, Fructose stimulated de novo lipogenesis is promoted by inflammation, Nature Metabolism, 2, (10) pp. 1034-1045. ISSN 2522-5812 (2020) [Refereed Article]

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2020 Springer Nature. Post-prints are subject to Springer Nature re-use terms

DOI: doi:10.1038/s42255-020-0261-2


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 Details

Item Type:Refereed Article
Keywords:immunometabolism, liver, diabetes, cancer, gut, inflammation
Research Division:Biological Sciences
Research Group:Biochemistry and cell biology
Research Field:Cell metabolism
Objective Division:Health
Objective Group:Clinical health
Objective Field:Clinical health not elsewhere classified
UTAS Author:Henstridge, DC (Dr Darren Henstridge)
ID Code:140535
Year Published:2020
Web of Science® Times Cited:105
Deposited By:Health Sciences
Deposited On:2020-08-26
Last Modified:2022-08-24
Downloads:18 View Download Statistics

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