Fructose stimulated de novo lipogenesis is promoted by inflammation

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

Additional file 23 of Integration of metabolomics, genomics, and immune phenotypes reveals the causal roles of metabolites in disease

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Additional file 11 of Integration of metabolomics, genomics, and immune phenotypes reveals the causal roles of metabolites in disease

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Additional file 18 of Integration of metabolomics, genomics, and immune phenotypes reveals the causal roles of metabolites in disease

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Additional file 17 of Integration of metabolomics, genomics, and immune phenotypes reveals the causal roles of metabolites in disease

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Additional file 3 of Integration of metabolomics, genomics, and immune phenotypes reveals the causal roles of metabolites in disease

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Additional file 15 of Integration of metabolomics, genomics, and immune phenotypes reveals the causal roles of metabolites in disease

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Additional file 9 of Integration of metabolomics, genomics, and immune phenotypes reveals the causal roles of metabolites in disease

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Additional file 9 of Integration of metabolomics, genomics, and immune phenotypes reveals the causal roles of metabolites in disease

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Additional file 6 of Integration of metabolomics, genomics, and immune phenotypes reveals the causal roles of metabolites in disease

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