October 5, 2006; doi:10.1152/ajpgi.00024.2006.-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.

In epithelial tissue, cell-matrix and cell-cell adhesive interactions have important roles in the normal organization and stabilization of the cell layer. The malignant conversion of epithelial cells involves alterations in the expression and function of these adhesion systems that enable a switch to a migratory phenotype in tumor invasion and metastasis. Fascin is an actin-crosslinking protein that is found in the core actin bundles of cell-surface spikes and projections that are implicated in cell motility. We demonstrate that fascin is not detectable in normal colonic epithelium, but is dramatically up-regulated in colorectal adenocarcinoma. To test the hypothesis that fascin could participate in tumor invasive behavior, we developed a cell culture model to examine the effect of fascin expression on the adhesive interactions, invasiveness, and differentiation of colonic epithelial cells. We report marked effects on the organization of cell-surface protrusions, actin cytoskeleton, and focal adhesions in the absence of alterations in the protein levels of the major components of these structures. These effects correlate with alterations in cell movements on two-dimensional matrix, and increased invasiveness in three-dimensional matrix. The cells also show increased proliferation and decreased capacity for normal glandular differentiation in collagen gels. We propose that up-regulation of fascin, by promoting the formation of protrusive, actin-based, cell-motility structures, could be a significant component in the acquisition of invasive phe- Epithelial cell differentiation is fundamentally influenced by cell-matrix and cell-cell interactions. [1][2][3] In colonic epithelial cells, both the integrin and cadherin superfamilies of adhesion molecules are important contributors to the establishment of cell polarity and epithelial cell differentiation, and have been shown to play a role in the control of colorectal differentiation in tumor cells. 4,5 This is partly achieved through the formation of intracellular protein assemblies that anchor cytoskeletal actin filaments at defined areas within the cell membrane. In epithelial cells, these zones correspond to integrin-dependent focal adhesions and cadherin-containing adherens junctions and desmosomes. 6 These assemblies also function as important links in the integration of multiple cell signaling pathways. 3 Cell-matrix and cell-cell adhesive interactions normally stabilize the epithelial cell layer and maintain the cells in a nonmigratory state. However, the malignant conversion of epithelial cells involves a phenotypic switch to a migratory state that enables tumor invasion beyond the basement membrane and metastasis. The process of cell migration is poorly understood in epithelial cells, but studies in many types of carcinoma cells have documented increased formation of cell protrusions at cell margins, release of cell-cell contacts, and group movement of sheets of cells. In the models of cell motility that have been developed from studies of fibroblasts, protru...

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Among the different drainage approaches in the non-surgical management of acute cholecystitis, EUS-guided transmural stenting for gallbladder drainage appears to be feasible, safe, and effective. LAMSs seem to have high potentials in terms of efficacy and safety, although further prospective studies are needed.