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

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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.

Original language	English
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
Publication status	Published - 24 Aug 2020

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10.1038/s42255-020-0261-2

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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

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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.",

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

note = "Funding Information: We thank M. Raffatellu for advice and discussion and V. Sheen, W. Gong, J. Yung and K. Lam for technical support. Research was supported by grants from the NIH (P42ES010337, R01DK120714, R01CA198103, R01AI043477, R01CA211794 and R01CA234128 to M.K.; R03CA223717 to J.T.; T32AI007469 and K22AI139444 to R.MN..; R01CA192642, R01CA218254 to M.T.D.-M.; R01DK108743, R01CA207177 and R01CA211794 to J.M.; U01AA027681 to S.S. and M.K.; and R01CA188652 to C.M.M.), JSPS KAKENHI (JP15K21775) and {\textquoteleft}Kibou Projects{\textquoteright} Startup Support for Young Researchers in Immunology (to K.T.), and the Australian NHMRC (APP112227) to M.A.F. and M.K.; work in F.R.G.{\textquoteright}s laboratory was supported by institutional funds from the Georg-Speyer-Haus and by the LOEWE Center Frankfurt Cancer Institute (FCI), funded by the Hessen State Ministry for Higher Education, Research and the Arts (III L 5 - 519/03/03.001 - (0015)), NIH K01DK116917 and P30DK063491 pilot award to J.D.W.; and S10OD020025, R01ES027595, and P42ES010337 to M.J. M.A.F. is a senior principal research fellow of the NHMRC Australia (APP 1116936). Publisher Copyright: {\textcopyright} 2020, The Author(s), under exclusive licence to Springer Nature Limited.",

year = "2020",

month = aug,

day = "24",

doi = "10.1038/s42255-020-0261-2",

language = "English",

volume = "2",

pages = "1034--1045",

journal = "Nature Metabolism",

issn = "2522-5812",

publisher = "Nature Publishing Group",

number = "10",

}

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

TY - JOUR

T1 - Fructose stimulated de novo lipogenesis is promoted by inflammation

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

N1 - Funding Information: We thank M. Raffatellu for advice and discussion and V. Sheen, W. Gong, J. Yung and K. Lam for technical support. Research was supported by grants from the NIH (P42ES010337, R01DK120714, R01CA198103, R01AI043477, R01CA211794 and R01CA234128 to M.K.; R03CA223717 to J.T.; T32AI007469 and K22AI139444 to R.MN..; R01CA192642, R01CA218254 to M.T.D.-M.; R01DK108743, R01CA207177 and R01CA211794 to J.M.; U01AA027681 to S.S. and M.K.; and R01CA188652 to C.M.M.), JSPS KAKENHI (JP15K21775) and ‘Kibou Projects’ Startup Support for Young Researchers in Immunology (to K.T.), and the Australian NHMRC (APP112227) to M.A.F. and M.K.; work in F.R.G.’s laboratory was supported by institutional funds from the Georg-Speyer-Haus and by the LOEWE Center Frankfurt Cancer Institute (FCI), funded by the Hessen State Ministry for Higher Education, Research and the Arts (III L 5 - 519/03/03.001 - (0015)), NIH K01DK116917 and P30DK063491 pilot award to J.D.W.; and S10OD020025, R01ES027595, and P42ES010337 to M.J. M.A.F. is a senior principal research fellow of the NHMRC Australia (APP 1116936). Publisher Copyright: © 2020, The Author(s), under exclusive licence to Springer Nature Limited.

PY - 2020/8/24

Y1 - 2020/8/24

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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U2 - 10.1038/s42255-020-0261-2

DO - 10.1038/s42255-020-0261-2

M3 - Article

C2 - 32839596

AN - SCOPUS:85089748086

SN - 2522-5812

VL - 2

SP - 1034

EP - 1045

JO - Nature Metabolism

JF - Nature Metabolism

IS - 10

ER -

Fructose stimulated de novo lipogenesis is promoted by inflammation

Abstract

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