Fructose stimulated de novo lipogenesis is promoted by inflammation

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

doi:10.1038/s42255-020-0261-2

Fructose stimulated de novo lipogenesis is promoted by inflammation

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

Research output: Contribution to journal › Article › peer-review

163 Scopus citations

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.

Original language	English (US)
Pages (from-to)	1034-1045
Number of pages	12
Journal	Nature Metabolism
Volume	2
Issue number	10
DOIs	https://doi.org/10.1038/s42255-020-0261-2
State	Published - Oct 1 2020
Externally published	Yes

ASJC Scopus subject areas

Internal Medicine
Endocrinology, Diabetes and Metabolism
Cell Biology
Physiology (medical)

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Todoric, J., Di Caro, G., Reibe, S., Henstridge, D. C., Green, C. R., Vrbanac, A., Ceteci, F., Conche, C., McNulty, R., Shalapour, S., Taniguchi, K., Meikle, P. J., Watrous, J. D., Moranchel, R., Najhawan, M., Jain, M., Liu, X., Kisseleva, T., Diaz-Meco, M. T., ... Karin, M. (2020). Fructose stimulated de novo lipogenesis is promoted by inflammation. Nature Metabolism, 2(10), 1034-1045. https://doi.org/10.1038/s42255-020-0261-2

Todoric, J, Di Caro, G, Reibe, S, Henstridge, DC, Green, CR, Vrbanac, A, Ceteci, F, Conche, C, McNulty, R, Shalapour, S, Taniguchi, K, Meikle, PJ, 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 & Karin, M 2020, 'Fructose stimulated de novo lipogenesis is promoted by inflammation', Nature Metabolism, vol. 2, no. 10, pp. 1034-1045. https://doi.org/10.1038/s42255-020-0261-2

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title = "Fructose stimulated de novo lipogenesis is promoted by inflammation",

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.",

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AU - Todoric, Jelena

AU - Di Caro, Giuseppe

AU - Reibe, Saskia

AU - Henstridge, Darren C.

AU - Green, Courtney R.

AU - Vrbanac, Alison

AU - Ceteci, Fatih

AU - Conche, Claire

AU - McNulty, Reginald

AU - Shalapour, Shabnam

AU - Taniguchi, Koji

AU - Meikle, Peter J.

AU - Watrous, Jeramie D.

AU - Moranchel, Rafael

AU - Najhawan, Mahan

AU - Jain, Mohit

AU - Liu, Xiao

AU - Kisseleva, Tatiana

AU - Diaz-Meco, Maria T.

AU - Moscat, Jorge

AU - Knight, Rob

AU - Greten, Florian R.

AU - Lau, Lester F.

AU - Metallo, Christian M.

AU - Febbraio, Mark A.

AU - Karin, Michael

PY - 2020/10/1

Y1 - 2020/10/1

N2 - 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.

AB - 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.

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ER -

Fructose stimulated de novo lipogenesis is promoted by inflammation

Abstract

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