Jelena Todoric1,2, Giuseppe Di Caro1, Saskia Reibe3, Darren C Henstridge4, Courtney R Green5, Alison Vrbanac6, Fatih Ceteci7,8,9, Claire Conche7,8,9, Reginald McNulty1,10, Shabnam Shalapour1, Koji Taniguchi1,11, Peter J Meikle4, Jeramie D Watrous12, Rafael Moranchel12, Mahan Najhawan12, Mohit Jain12, Xiao Liu12, Tatiana Kisseleva12, Maria T Diaz-Meco13, Jorge Moscat13, Rob Knight14, Florian R Greten7,8,9, Lester F Lau15, Christian M Metallo5, Mark A Febbraio16, Michael Karin17. 1. Laboratory of Gene Regulation and Signal Transduction, Department of Pharmacology, School of Medicine, University of California San Diego, La Jolla, CA, USA. 2. Department of Laboratory Medicine, Medical University of Vienna, Vienna, Austria. 3. Garvan Institute of Medical Research, Sydney, Australia. 4. Baker Heart and Diabetes Institute, Melbourne, Victoria, Australia. 5. Department of Bioengineering, University of California, San Diego, La Jolla, CA, USA. 6. Biomedical Sciences Graduate Program, University of California San Diego, La Jolla, CA, USA. 7. Institute for Tumor Biology and Experimental Therapy, Georg-Speyer-Haus, Frankfurt/Main, Germany. 8. Frankfurt Cancer Institute, Goethe University Frankfurt, Frankfurt/Main, Germany. 9. German Cancer Consortium (DKTK) and German Cancer Research Center (DKFZ), Heidelberg, Germany. 10. Department of Molecular Biology and Biochemistry, University of California Irvine, Irvine, CA, USA. 11. Department of Microbiology and Immunology, Keio University School of Medicine, Tokyo, Japan. 12. Departments of Medicine and Pharmacology, University of California San Diego, La Jolla, CA, USA. 13. Cancer Metabolism and Signaling Networks Program, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA, USA. 14. Department of Pediatrics, Department of Computer Science and Engineering, Department of Bioengineering, and The Center for Microbiome Innovation, University of California, San Diego, La Jolla, CA, USA. 15. Department of Biochemistry and Molecular Genetics, University of Illinois at Chicago College of Medicine, Chicago, IL, USA. 16. Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria, Australia. 17. Laboratory of Gene Regulation and Signal Transduction, Department of Pharmacology, School of Medicine, University of California San Diego, La Jolla, CA, USA. karinoffice@ucsd.edu.
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.
n class="Disease">Benign hepatosteatosis, affected by pan> class="Chemical">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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