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1 Histology, Microbiology and Medical Biotechnologies, University of Padua, Padua, Italy; Gastroenterological Sciences, University of Padua, Padua, Italy
2 Histology, Microbiology and Medical Biotechnologies, University of Padua, Padua, Italy
3 Gastroenterological Sciences, University of Padua, Padua, Italy
4 Internal Medicine, University of Florence, Florence, Italy
* To whom correspondence should be addressed. E-mail: ignazio.castagliuolo{at}unipd.it.
Background & Aims: A small percentage of pathologically obese subjects with fatty liver develops histological signs of necroinflammation and fibrosis, suggesting a variety of cofactors in the pathogenesis of obesity-related liver diseases including nonalcoholic steatohepatitis (NASH). 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). Methods: Murine intestinal mucosal barrier function was assessed by Ussing chamber whereas ileum tight junctions (TJ) proteins were analyzed by immunocytochemistry and Western blotting. Circulating pro-inflammatory cytokines and portal blood endotoxin levels were measured by ELISA and Limulus test, respectively. The inflammatory and fibrogenic phenotype of murine hepatic stellate cells (HSCs) was determined by ELISA and quantitative RT-PCR. Results: Ob/ob and db/db mice showed lower intestinal resistance, profoundly modified distribution of occludin and ZO-1 in the intestinal mucosa and higher circulating levels of inflammatory cytokines and portal endotoxemia as compared to lean control mice. Moreover, HSCs isolated from ob/ob and db/db mice showed higher mCD14 mRNA levels and more pronounced LPS-induced pro-inflammatory and fibrogenic responses than HSCs from lean animals. Conclusions: 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 LPS levels in portal blood that can contribute to the liver inflammatory damage.
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