Fructose-induced steatosis in mice: role of plasminogen activator inhibitor-1, microsomal triglyceride transfer protein and NKT cells

Plasminogen activator inhibitor-1 (PAI-1) is an acute-phase protein known to be involved in alcoholic liver disease and hepatic fibrosis. In the present study, the hypothesis that PAI-1 is causally involved in the onset of fructose-induced hepatic steatosis was tested in a mouse model. Wild-type C57BL/6J and PAI-1-/- mice were fed with 30% fructose solution or water for 8 weeks. Markers of hepatic steatosis, expression of PAI-1, apolipoprotein B (ApoB), cluster of differentiation 1d (CD1d), markers of natural killer T (NKT) cells, protein levels of phospho-c-Met and tumor necrosis factor-alpha (TNF-alpha) were determined. Activity of the microsomal triglyceride transfer protein (MTTP) was measured in liver tissue. In comparison with water controls, chronic intake of 30% fructose solution caused a significant increase in hepatic triglycerides, PAI-1 expression and plasma alanine aminotransferase levels in wild-type mice. This effect of fructose feeding was markedly attenuated in PAI-1-/- mice. Despite no differences in portal endotoxin levels and hepatic TNF-alpha protein levels between fructose-fed groups, the protective effect of the loss of PAI-1 against the onset of fructose-induced steatosis was associated with a significant increase in phospho-c-Met, phospho Akt, expression of ApoB and activity of MTTP in livers of PAI-1-/- mice in comparison with fructose-fed wild types. Moreover, in PAI-1-/- mice, expressions of CD1d and markers of CD1d-reactive NKT cells were markedly higher than in wild-type mice; however, expression of markers of activation of CD1d-reactive NKT cells (eg, interleukin-15 and interferon-gamma) were only found to be increased in livers of fructose-fed PAI-1-/- mice. Taken together, these data suggest that PAI-1 has a causal role in mediating the early phase of fructose-induced liver damage in mice through signaling cascades downstream of Kupffer cells and TNF-alpha. Laboratory Investigation (2011) 91, 885-895; doi:10.1038/labinvest.2011.44; published online 21 March 2011