title: Increased intestinal permeability in obese mice: new evidence in the pathogenesis of nonalcoholic steatohepatitis.
abstract: A small percentage of pathologically obese subjects with fatty livers develop histological signs of necroinflammation and fibrosis, suggesting a variety of cofactors in the pathogenesis of obesity-related liver diseases including nonalcoholic steatohepatitis. Since several observations have linked bacterial endotoxins to liver damage, the aim of this study was to determine the effect of obesity on intestinal mucosal integrity and portal blood endotoxemia in two strains of obese mice: leptin-deficient (ob/ob) and hyperleptinemic (db/db) mice. Murine intestinal mucosal barrier function was assessed using a Ussing chamber, whereas ileum tight junction proteins were analyzed by immunocytochemistry and Western blot analysis. Circulating proinflammatory cytokines and portal blood endotoxin levels were measured by ELISA and the limulus test, respectively. The inflammatory and fibrogenic phenotype of murine hepatic stellate cells (HSCs) was determined by ELISA and quantitative RT-PCR. Ob/ob and db/db mice showed lower intestinal resistance, profoundly modified distribution of occludin and zonula occludens-1 in the intestinal mucosa, and higher circulating levels of inflammatory cytokines and portal endotoxemia compared with lean control mice. Moreover, HSCs isolated from ob/ob and db/db mice showed higher membrane CD14 mRNA levels and more pronounced lipopolysaccharide-induced proinflammatory and fibrogenic responses than HSCs from lean animals. In conclusion, genetically obese mice display enhanced intestinal permeability leading to increased portal endotoxemia that makes HSCs more sensitive to bacterial endotoxins. We suggest that in metabolic syndrome, patients may likewise have a greater intestinal mucosa permeability and increased lipopolysaccharide levels in portal blood that can contribute to the liver inflammatory damage.
authors.affiliation: Department of Histology, Univ of Padua, Via Gabelli 63, Padova, Italy.
authors.forename: Paola
authors.initials: P
authors.lastname: Brun
authors.forename: Ignazio
authors.initials: I
authors.lastname: Castagliuolo
authors.forename: Vincenza
authors.initials: V
authors.lastname: Di Leo
authors.forename: Andrea
authors.initials: A
authors.lastname: Buda
authors.forename: Massimo
authors.initials: M
authors.lastname: Pinzani
authors.forename: Giorgio
authors.initials: G
authors.lastname: Palù
authors.forename: Diego
authors.initials: D
authors.lastname: Martines
mesh_terms: D000818:Animals; D001786:Blood Glucose / Q000032:analysis; D018932:Chemokine CCL2 / Q000235:genetics / Q000378:metabolism; D024042:Collagen Type I / Q000235:genetics; D005234:Fatty Liver / Q000209:etiology / Q000503:physiopathology*; D005353:Fibronectins / Q000235:genetics; D015870:Gene Expression / Q000187:drug effects; D007371:Interferon-gamma / Q000097:blood; D053583:Interleukin-1beta / Q000097:blood; D015850:Interleukin-6 / Q000097:blood / Q000235:genetics / Q000378:metabolism; D007413:Intestinal Mucosa / Q000378:metabolism* / Q000503:physiopathology; D007421:Intestine, Small / Q000378:metabolism* / Q000503:physiopathology; D020738:Leptin / Q000235:genetics; D008070:Lipopolysaccharides / Q000097:blood / Q000494:pharmacology; D008099:Liver / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008820:Mice, Obese; D009765:Obesity / Q000150:complications / Q000235:genetics / Q000378:metabolism*; D010539:Permeability; D011169:Portal Vein / Q000737:chemistry; D011956:Receptors, Cell Surface / Q000235:genetics; D054411:Receptors, Leptin; D014409:Tumor Necrosis Factor-alpha / Q000097:blood
chemical_list: D001786:Blood Glucose; C491768:Ccl2 protein, mouse; D018932:Chemokine CCL2; D024042:Collagen Type I; D005353:Fibronectins; D053583:Interleukin-1beta; D015850:Interleukin-6; D020738:Leptin; D008070:Lipopolysaccharides; D011956:Receptors, Cell Surface; D054411:Receptors, Leptin; D014409:Tumor Necrosis Factor-alpha; D007371:Interferon-gamma