The proinflammatory phenotype of PECAM-1-deficient mice results in atherogenic diet-induced steatohepatitis.
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.
Goel
Reema
R
Blood Research Institute, BloodCenter of Wisconsin, P.O. Box 2178, Milwaukee, WI 53201, USA. reema.goel@bcw.edu
Boylan
Brian
B
Gruman
Lynn
L
Newman
Peter J
PJ
North
Paula E
PE
Newman
Debra K
DK
D000818:Animals; D050197:Atherosclerosis / Q000378:metabolism* / Q000473:pathology*; D004036:Diet, Atherogenic; D006505:Hepatitis / Q000378:metabolism* / Q000473:pathology*; D007155:Immunologic Factors / Q000378:metabolism; D008099:Liver / Q000378:metabolism* / Q000473:pathology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010641:Phenotype; D019408:Platelet Endothelial Cell Adhesion Molecule-1 / Q000235:genetics / Q000378:metabolism*; D013231:Steatitis / Q000378:metabolism / Q000473:pathology
D007155:Immunologic Factors; D019408:Platelet Endothelial Cell Adhesion Molecule-1