Nonalcoholic Fatty Liver Disease in Humans Is Associated with Increased Plasma Endotoxin and Plasminogen Activator Inhibitor 1 Concentrations and with Fructose Intake

Abstract

Results of animal experiments suggest that consumption of refined carbohydrates (e.g. fructose) can result in small intestinal bacterial overgrowth and increased intestinal permeability, thereby contributing to the development of nonalcoholic fatty liver disease (NAFLD). Furthermore, increased plasminogen activator inhibitor (PAI)-1 has been linked to liver damage of various etiologies (e.g. alcohol, endotoxin, nonalcoholic). The aim of the present pilot study was to compare dietary factors, endotoxin, and PAI-1 concentrations between NAFLD patients and controls. We assessed the dietary intake of 12 patients with NAFLD and 6 control subjects. Plasma endotoxin and PAI-1 concentrations as well as hepatic expression of PAI-1 and toll-like receptor (TLR) 4 mRNA were determined. Despite similar total energy, fat, protein, and carbohydrate intakes, patients with NAFLD consumed significantly more fructose than controls. Endotoxin and PAI-1 plasma concentrations as well as hepatic TLR4 and PAI-1 mRNA expression of NAFLD patients were significantly higher than in controls. The plasma PAI-1 concentration was positively correlated with the plasma endotoxin concentration (Spearman r = 0.83; P < 0.005) and hepatic TLR4 mRNA expression (Spearman r = 0.54; P < 0.05). Hepatic mRNA expression of PAI-1 was positively associated with dietary intakes of carbohydrates (Spearman r = 0.67; P < 0.01), glucose (Spearman r = 0.58; P < 0.01), fructose (Spearman r = 0.58; P < 0.01), and sucrose (Spearman r = 0.70; P < 0.01). In conclusion, our results suggest that dietary fructose intake, increased intestinal translocation of bacterial endotoxin, and PAI-1 may contribute to the development of NAFLD in humans.

Toll-like receptor 4 is involved in the development of fructose-induced hepatic steatosis in mice

“…Rather, our results suggest that an increased intestinal translocation of bacterial endotoxin and subsequent activation of Kupffer cells through a TLR-4-dependent mechanism mediated through MyD88-dependent signaling pathways may also partially add or even enhance the development of this liver disease (e.g., through causing insulin resistance). These findings are also in line with results of recent human studies 6,7 suggesting that in patients with NAFLD, both dietary fructose intake and plasma endotoxin levels are elevated in comparison to controls. However, additional studies will be necessary to further explore underlying mechanisms and possible resulting therapeutic strategies (e.g., fructose avoidance therapy, treatment with antibiotics).…”

“…4,5 Furthermore, it has recently been shown that in patients with NAFLD (e.g., with simple steatosis and steatohepatitis with begin-ning fibrosis) intake of fructose is markedly higher than in controls. 6,7 In line with these findings it has been shown in animal studies that an increased consumption of fructose (e.g., up to 60% of daily calories derived from fructose) may result in hepatic steatosis accompanied by insulin resistance, elevated plasma triglyceride levels, and oxidative stress in the liver. [8][9][10][11] In addition, we recently showed that even the early stages of fructose-induced NAFLD (e.g., steatosis) are associated with an increased intestinal translocation of bacterial endotoxin, formation of 4-hydroxynonenal adduct formation, and expression of tumor necrosis factor alpha (TNF␣) in the liver.…”

Toll-like receptor 4: A starting point for proinflammatory signals in fatty liver disease

“…In particular, a recent work 4 demonstrates that patients with NAFLD have a significantly greater consumption of fructose than controls, and an increased hepatic expression of fructokinase messenger RNA. Although the role of TLR-4 in carbohydratedependent NAFLD has been only recently suggested by Thuy and colleagues, 5 they have pinpointed one of the potential mechanisms through which fructose could participate in NAFLD development and progression in humans: a carbohydrate-rich diet may produce ethanol when intestinal stasis favors bacterial overgrowth in the upper parts of the gastrointestinal tract. The increased portal endotoxemia could initiate TLR signaling and induce necroinflammation, which characterizes steatohepatitis, the most advanced form of NAFLD.…”

“…We assessed the ability of these two indexes and of plasma cytokeratin-18 fragments (CK-18) to predict the presence of nonalcoholic fatty liver disease (NAFLD) and of nonalcoholic steatohepatitis (NASH), 1,2 respectively, and their relations to validated predictors of incident cardiovascular disease and diabetes. 3,4 To this purpose, 125 subjects (40 nondiabetic patients with biopsyproven NAFLD and 85 healthy controls) underwent an oral fat tolerance test, 5 with measurement of postprandial plasma lipid responses, and a standard oral glucose tolerance test (OGTT), whose results were elaborated by Minimal Model analysis to assess whole-body, hepatic, and muscle insulin sensitivity and indexes of pancreatic ␤-cell function (namely, CP-genic index [CGI] and Adaptation Index [AI]), as previously described. [5][6][7] Finally, circulating markers of inflammation (Creactive protein), endothelial dysfunction (E-selectin and intercellular adhesion molecule-1 [ICAM-1]) and oxidative stress (nitrotyrosine and oxidized low-density lipoproteins) were measured.…”

“…It is time to establish the feasibility and safety of TIPS for cirrhotic PVT and thereby design prospective studies, although we have to acknowledge the technical difficulty of TIPS with thrombectomy for PVT: only 28 cases have been studied retrospectively in the largest series 5 …”