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 journalArticlepeer-review

26 Citations (Scopus)

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 languageEnglish
Pages (from-to)1034-1045
Number of pages12
JournalNature Metabolism
Volume2
Issue number10
DOIs
Publication statusPublished - 2020 Oct 1

ASJC Scopus subject areas

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

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