title: Fructose-induced steatosis in mice: role of plasminogen activator inhibitor-1, microsomal triglyceride transfer protein and NKT cells.
abstract: 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-α (TNF-α) 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-α 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-γ) 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-α.
authors.affiliation: Department of Nutritional Medicine (180 a), University of Hohenheim, Stuttgart, Germany.
authors.forename: Giridhar
authors.initials: G
authors.lastname: Kanuri
authors.forename: Astrid
authors.initials: A
authors.lastname: Spruss
authors.forename: Sabine
authors.initials: S
authors.lastname: Wagnerberger
authors.forename: Stephan C
authors.initials: SC
authors.lastname: Bischoff
authors.forename: Ina
authors.initials: I
authors.lastname: Bergheim
mesh_terms: D000410:Alanine Transaminase / Q000097:blood; D000704:Analysis of Variance; D000818:Animals; D055610:Antigens, CD1d / Q000378:metabolism; D001055:Apolipoproteins B / Q000378:metabolism; D015415:Biomarkers / Q000378:metabolism; D002352:Carrier Proteins / Q000378:metabolism*; D002478:Cells, Cultured; D017931:DNA Primers / Q000235:genetics; D005234:Fatty Liver / Q000139:chemically induced*; D005632:Fructose / Q000008:administration & dosage / Q000009:adverse effects*; D015151:Immunoblotting; D007150:Immunohistochemistry; D007694:Killer Cells, Natural / Q000378:metabolism*; D007728:Kupffer Cells / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D017395:Plasminogen Activator Inhibitor 1 / Q000235:genetics / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014280:Triglycerides / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
chemical_list: D055610:Antigens, CD1d; D001055:Apolipoproteins B; D015415:Biomarkers; D002352:Carrier Proteins; C526879:Cd1d1 protein, mouse; D017931:DNA Primers; D017395:Plasminogen Activator Inhibitor 1; D014280:Triglycerides; D014409:Tumor Necrosis Factor-alpha; C106092:microsomal triglyceride transfer protein; D005632:Fructose; D000410:Alanine Transaminase