title: Diets rich in fructose, fat or fructose and fat alter intestinal barrier function and lead to the development of nonalcoholic fatty liver disease over time.
abstract: General overnutrition but also a diet rich in certain macronutrients, age, insulin resistance and an impaired intestinal barrier function may be critical factors in the development of nonalcoholic fatty liver disease (NAFLD). Here the effect of chronic intake of diets rich in different macronutrients, i.e. fructose and/or fat on liver status in mice, was studied over time. C57BL/6J mice were fed plain water, 30% fructose solution, a high-fat diet or a combination of both for 8 and 16 weeks. Indices of liver damage, toll-like receptor 4 (TLR-4) signaling cascade, macrophage polarization and insulin resistance in the liver and intestinal barrier function were analyzed. Chronic exposure to a diet rich in fructose and/or fat was associated with the development of hepatic steatosis that progressed with time to steatohepatitis in mice fed a combination of macronutrients. The development of NAFLD was also associated with a marked reduction of the mRNA expression of insulin receptor, whereas hepatic expressions of TLR-4, myeloid differentiation primary response gene 88 and markers of M1 polarization of macrophages were induced in comparison to controls. Bacterial endotoxin levels in portal plasma were found to be increased while levels of the tight junction protein occludin and zonula occludens 1 were found to be significantly lower in the duodenum of all treated groups after 8 and 16 weeks. Our data suggest that chronic intake of fructose and/or fat may lead to the development of NAFLD over time and that this is associated with an increased translocation of bacterial endotoxin.
authors.affiliation: Institute of Nutritional Sciences, Model Systems of Molecular Nutrition, Friedrich-Schiller-University Jena, Jena, Germany.
authors.forename: Cathrin
authors.initials: C
authors.lastname: Sellmann
authors.affiliation: Institute of Nutritional Sciences, Model Systems of Molecular Nutrition, Friedrich-Schiller-University Jena, Jena, Germany.
authors.forename: Josephine
authors.initials: J
authors.lastname: Priebs
authors.affiliation: Institute of Nutritional Sciences, Model Systems of Molecular Nutrition, Friedrich-Schiller-University Jena, Jena, Germany.
authors.forename: Marianne
authors.initials: M
authors.lastname: Landmann
authors.affiliation: Institute of Nutritional Sciences, Model Systems of Molecular Nutrition, Friedrich-Schiller-University Jena, Jena, Germany.
authors.forename: Christian
authors.initials: C
authors.lastname: Degen
authors.affiliation: Institute of Nutritional Sciences, Model Systems of Molecular Nutrition, Friedrich-Schiller-University Jena, Jena, Germany.
authors.forename: Anna Janina
authors.initials: AJ
authors.lastname: Engstler
authors.affiliation: Institute of Nutritional Sciences, Model Systems of Molecular Nutrition, Friedrich-Schiller-University Jena, Jena, Germany.
authors.forename: Cheng Jun
authors.initials: CJ
authors.lastname: Jin
authors.affiliation: Institute of Nutritional Sciences, Model Systems of Molecular Nutrition, Friedrich-Schiller-University Jena, Jena, Germany.
authors.forename: Stefanie
authors.initials: S
authors.lastname: Gärttner
authors.affiliation: Department of Nutritional Medicine, University of Hohenheim, Stuttgart, Germany.
authors.forename: Astrid
authors.initials: A
authors.lastname: Spruss
authors.affiliation: Department of Biochemistry II, University Hospital Jena, Friedrich-Schiller-University Jena, Jena, Germany; Center of Sepsis Control and Care, Jena University Hospital, Jena, Germany.
authors.forename: Otmar
authors.initials: O
authors.lastname: Huber
authors.affiliation: Institute of Nutritional Sciences, Model Systems of Molecular Nutrition, Friedrich-Schiller-University Jena, Jena, Germany. Electronic address: ina.bergheim@uni-jena.de.
authors.forename: Ina
authors.initials: I
authors.lastname: Bergheim
mesh_terms: D000447:Aldehydes / Q000378:metabolism; D000818:Animals; D001835:Body Weight / Q000187:drug effects; D059305:Diet, High-Fat / Q000009:adverse effects*; D004731:Endotoxins / Q000097:blood; D002149:Energy Intake / Q000187:drug effects; D005260:Female; D005632:Fructose / Q000009:adverse effects*; D007333:Insulin Resistance; D007413:Intestinal Mucosa / Q000378:metabolism; D007422:Intestines / Q000187:drug effects / Q000503:physiopathology*; D008099:Liver / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D008810:Mice, Inbred C57BL; D053594:Myeloid Differentiation Factor 88 / Q000235:genetics; D052247:Nitric Oxide Synthase Type II / Q000378:metabolism; D065626:Non-alcoholic Fatty Liver Disease / Q000209:etiology*; D062725:Tight Junction Proteins / Q000378:metabolism; D051197:Toll-Like Receptor 4 / Q000235:genetics
chemical_list: D000447:Aldehydes; D004731:Endotoxins; C507780:Myd88 protein, mouse; D053594:Myeloid Differentiation Factor 88; D062725:Tight Junction Proteins; C493487:Tlr4 protein, mouse; D051197:Toll-Like Receptor 4; D005632:Fructose; D052247:Nitric Oxide Synthase Type II; C496317:Nos2 protein, mouse; C027576:4-hydroxy-2-nonenal
keywords: Aging; Endotoxin; Macronutrients; NAFLD; Tight junction