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

Medical College of Wisconsin, Milwaukee, Wisconsin, United States
AJP Gastrointestinal and Liver Physiology (Impact Factor: 3.8). 01/2008; 293(6):G1205-14. DOI: 10.1152/ajpgi.00157.2007
Source: PubMed


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-alpha 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.

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    • "Platelet/endothelial cell adhesion molecule 1 (Pecam1) is a glycoprotein located near a QTL for fatty liver [32] and diabetes [30]. Previous work has suggested that Pecam1 is involved in regulating inflammation and higher expression of this gene protects the liver from the effect of high dietary fat and NAFLD [57]. High-fat fed SM/J displayed significantly higher Pecam1 expression levels when compared to low-fat fed individuals. "
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    • "Since PECAM-1 did not inhibit cellular cytokine synthesis (Figs. 2 and 3), we next examined whether PECAM-1 regulates cytokine levels through leukocyte trafficking and accumulation. Previous studies have demonstrated that mice expressing PECAM-1 have decreased accumulation of leukocytes at inflammatory sites during EAE (Graesser et al. 2002), collagen-induced arthritis (Tada et al. 2003), atherogenic diet-induced steatohepatitis (Goel et al. 2007), and LPS-induced endotoxemia (Maas et al. 2005), with the latter three studies also reporting that PECAM-1 lowered systemic levels of pro-inflammatory cytokines (Tada et al. 2003; Maas et al. 2005; Goel et al. 2007). In the current study, we found that the lungs of PECAM-1-deficient mice, compared to wild-type mice, contained significantly more leukocytes, mainly macrophages and neutrophils, with a concomitant increase in IL-6 levels following LPS-injection (Fig. 4). "
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