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Browsing by Subject "Fruktose"

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    Role of plasminogen activator inhibitor (PAI-1) in the pathogenesis of fructose-induced non-alcoholic fatty liver disease (NAFLD)
    (2012) Kanuri, Giridhar; Bischoff, Stephan C.
    Non-alcoholic fatty liver disease (NAFLD), a liver disease frequently associated with obesity, type 2 diabetes and dyslipidemia has become a worldwide health problem during the last decades. Results of recent studies suggest that a diet rich in fructose may also be a risk factor for the development of NAFLD. Results of our own group but also other group suggest that TNFα and PAI-1 may be involved in the development of NAFLD in rodents but also humans. Therefore, the aim of the present study was to investigate the role TNFα and PAI-1 in the onset of fructose-induced NAFLD in a mouse model as well as in human NAFLD patients. The specific aims were 1) Are TNFR1-/- mice protected from fructose-induced NAFLD? If yes, what are the molecular mechanisms involved? TNFR1 -/- and wild-type mice were either fed 30% fructose solution or tap water. Chronic fructose feeding caused a significant ~5-fold increase in triglyceride accumulation and neutrophil infiltration in livers of wild-type mice and an ~8-fold increase in plasma alanine aminotransferase (ALT) levels in comparison to control mice. Similar effects of fructose feeding were not found in TNFR 1-/- mice. Indeed, the protective effect of the tumor necrosis factor receptor 1 (TNFR1) deletion against the onset of fructose-induced steatosis was associated with decreased sterol regulatory element-binding protein 1 (SREBP-1), fatty acid synthase (FAS) and plasminogen activator inhibitor 1 (PAI-1) expression in the liver. Furthermore, the protective effect was also associated with protection against alterations markers of insulin signaling cascade (e.g. adenosine monophosphate-activated protein kinase (AMPK), protein kinase B (Akt) levels). However, markers of hepatic lipid peroxidation, inducible nitric oxide synthase (iNOS) protein and adenosine triphosphate (ATP) levels were similar between wild-type and TNFR1 -/- mice fed fructose. Taken together, these data suggest that TNFα plays a casual role in the onset of fructose-induced liver damage as well as insulin resistance in mice through signaling cascades downstream of TNFR1. 2) Are PAI-1-/- mice protected from fructose-induced NAFLD? And if so, what are the molecular mechanisms involved? To address if PAI-1 is also a critical factor in the onset of fructose-induced NAFLD, PAI-1-/- and wild-type mice were either fed a fructose solution or tap water. Chronic fructose feeding in wild-type mice caused a marked increase in hepatic triglycerides, PAI-1 expression and plasma ALT levels in comparison to water controls. A similar effect of fructose feeding was not found in PAI-1-/- mice. PAI-1-/- mice fed fructose were protected from hepatic steatosis despite similar portal endotoxin levels, alterations of markers of insulin resistance and hepatic TNFα 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-cMet, phospho Akt, expression of apolipoprotein B (ApoB) and activity of microsomal triglyceride transfer protein (MTTP) in livers of PAI-1-/- mice in comparison to fructose fed wild-type mice. Moreover, in PAI-1-/- mice expression of CD1d and markers of CD1d-reactive iNKT cells were markedly higher than in wild-type mice; however, expression of markers of activation of CD1d-reactive iNKT cells (e.g. interleukin 15 (IL-15) and interferon γ (INFγ)) were only found to be increased in livers of fructose fed PAI-1-/- mice. Taken together, these data suggest that PAI-1 plays a causal role in mediating the early phase of fructose-induced liver damage in mice through signalling cascades down-stream of Kupffer cells and TNFα. 3) Are molecular mechanisms identified in mouse studies also relevant to human situation? To determine if the alterations found in livers of animals with NAFLD are also relevant in humans with NAFLD, markers of lipid peroxidation, insulin signaling and number of iNKT cells were determined in 6 controls and 11 NAFLD patients.4-hydroxynonenal (4-HNE) protein adducts levels were significantly higher in livers of NAFLD patients whereas expression of insulin receptor substrate (IRS-1) was reduced by ~80 % in comparison to controls. PAI-1 protein levels primarily found in hepatocytes was significantly higher in NAFLD patients; however, hepatic CD1d and MTTP mRNA expression did not differ between groups. Hepatic c-Met and BCL-2l mRNA expressions were significantly lower in NAFLD patients in comparison to controls and number of CD3ζ positive cells was higher. In contrast, expression of iNKT cell markers (e.g. IL-4 and IL-15) was significantly lower in livers of patients with NAFLD when compared with controls.Taken together, the present study suggests that the molecular mechanism involved in the progression of NAFLD is similar in both rodents and humans. Furthermore, TNFα and PAI-1 may be considered as therapeutic targets for NAFLD.