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This Article Full Text Full Text (PDF) All Versions of this Article: 293/6/G1205    most recent 00157.2007v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in ISI Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Google Scholar Articles by Goel, R. Articles by Newman, D. K. PubMed PubMed Citation Articles by Goel, R. Articles by Newman, D. K.

INFLAMMATION/IMMUNITY/MEDIATORS

The proinflammatory phenotype of PECAM-1-deficient mice results in atherogenic diet-induced steatohepatitis

¹Blood Research Institute, BloodCenter of Wisconsin, Milwaukee, Wisconsin; ²The Department of Pathology and Laboratory Medicine, Children's Hospital of Wisconsin, Milwaukee, Wisconsin; Departments of ³Pathology, ⁴Cell Biology, Neurobiology and Anatomy, ⁵Pharmacology, and ⁶Microbiology and Molecular Genetics, and ⁷The Cardiovascular Center, Medical College of Wisconsin, Milwaukee, Wisconsin

Submitted 11 April 2007 ; accepted in final form 2 October 2007

The severity of nonalcoholic steatohepatitis (NASH) is determined by environmental and genetic factors, the latter of which are incompletely characterized. Platelet endothelial cell adhesion molecule-1 (PECAM-1) is a 130-kDa transmembrane glycoprotein expressed on blood and vascular cells. In the present study, we provide data for the novel finding that genetic deficiency of PECAM-1 potentiates the development and progression of NASH. We found that the rate of development and severity of diet-induced NASH are markedly enhanced in PECAM-1-deficient [knockout (KO)] mice relative to wild-type (WT) mice, as measured by histological and biochemical evaluation. Livers from KO mice exhibited typical histological features of NASH, including macrovesicular fat accumulation, hepatocyte injury with infiltration of inflammatory cells, fibrosis, and heightened oxidative stress. Alanine aminotransferase, a marker for liver injury, was also significantly higher in KO compared with WT mice. Consistent with a role for PECAM-1 as a suppressor of proinflammatory cytokines, plasma levels of inflammatory cytokines, including TNF- and monocyte chemoattractant protein-1 (MCP-1), were also significantly higher in KO compared with WT mice. These findings are the first to show that the PECAM-1-deficient mouse develops progressive nonalcoholic fatty liver disease (NAFLD), supporting a role for PECAM-1 as a negative regulator of NAFLD progression. Future examination of recently identified PECAM-1 allelic isoforms in humans as potential risk factors for developing NASH may be warranted.

CD31; liver; NASH; inflammation