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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
  • And 6 more
Publication Date
Oct 01, 2020
Source
eScholarship - University of California
Keywords
License
Unknown
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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.

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