Title | Fructose stimulated de novo lipogenesis is promoted by inflammation. |
Publication Type | Journal Article |
Year of Publication | 2020 |
Authors | 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 |
Journal | Nat Metab |
Volume | 2 |
Issue | 10 |
Pagination | 1034-1045 |
Date Published | 2020 10 |
ISSN | 2522-5812 |
Keywords | Acetyl Coenzyme A, Animals, Endotoxemia, Female, Fructose, Fructosephosphates, Gastrointestinal Microbiome, Hepatocytes, Humans, Inflammation, Intestines, Lipidomics, Lipogenesis, Macrophages, Mice, Mice, Inbred C57BL, Non-alcoholic Fatty Liver Disease, Regeneration, Toll-Like Receptors |
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. |
DOI | 10.1038/s42255-020-0261-2 |
Alternate Journal | Nat Metab |
PubMed ID | 32839596 |
PubMed Central ID | PMC8018782 |
Grant List | R01 DK108743 / DK / NIDDK NIH HHS / United States R03 CA223717 / CA / NCI NIH HHS / United States R01 DK120714 / DK / NIDDK NIH HHS / United States P42 ES010337 / ES / NIEHS NIH HHS / United States R01 CA211794 / CA / NCI NIH HHS / United States S10 OD020025 / OD / NIH HHS / United States T32 AI007469 / AI / NIAID NIH HHS / United States P30 DK063491 / DK / NIDDK NIH HHS / United States R01 CA188652 / CA / NCI NIH HHS / United States U01 AA027681 / AA / NIAAA NIH HHS / United States R01 AI043477 / AI / NIAID NIH HHS / United States R01 CA198103 / CA / NCI NIH HHS / United States R01 CA192642 / CA / NCI NIH HHS / United States R01 CA218254 / CA / NCI NIH HHS / United States R01 ES027595 / ES / NIEHS NIH HHS / United States K22 AI139444 / AI / NIAID NIH HHS / United States R01 CA207177 / CA / NCI NIH HHS / United States K01 DK116917 / DK / NIDDK NIH HHS / United States R01 CA234128 / CA / NCI NIH HHS / United States |
Related Faculty:
Jorge Moscat, Ph.D. Maria Diaz-Meco Conde, Ph.D.