Toll-like receptor 4 is involved in the development of fructose-induced hepatic steatosis in mice.
A link between dietary fructose intake, gut-derived endotoxemia, and nonalcoholic fatty liver disease (NAFLD) has been suggested by the results of human and animal studies. To further investigate the role of gut-derived endotoxin in the onset of fructose-induced NAFLD, Toll-like receptor (TLR-) 4-mutant (C3H/HeJ) mice and wildtype (C3H/HouJ) mice were either fed plain water or water enriched with 30% fructose for 8 weeks. Hepatic steatosis, plasma alanine aminotransferase (ALT), and markers of insulin resistance as well as portal endotoxin levels were determined. Hepatic levels of myeloid differentiation factor 88 (MyD88), interferon regulatory factor (IRF) 3 and 7, and tumor necrosis factor alpha (TNFalpha) as well as markers of lipid peroxidation were assessed. Chronic intake of 30% fructose solution caused a significant increase in hepatic steatosis and plasma ALT levels in wildtype animals in comparison to water controls. In fructose-fed TLR-4 mutant mice, hepatic triglyceride accumulation was significantly reduced by approximately 40% in comparison to fructose-fed wildtype mice and plasma ALT levels were at the level of water-fed controls. No difference in portal endotoxin concentration between fructose-fed wildtype and TLR-4-mutant animals was detected. In contrast, hepatic lipid peroxidation, MyD88, and TNFalpha levels were significantly decreased in fructose-fed TLR-4-mutant mice in comparison to fructose-fed wildtype mice, whereas IRF3 and IRF7 expression remained unchanged. Markers of insulin resistance (e.g., plasma TNFalpha, retinol binding protein 4, and hepatic phospho-AKT) were only altered in fructose-fed wildtype animals.


CONCLUSIONS
Taken together, these data further support the hypothesis that in mice the onset of fructose-induced NAFLD is associated with intestinal bacterial overgrowth and increased intestinal permeability, subsequently leading to an endotoxin-dependent activation of hepatic Kupffer cells.
Spruss
Astrid
A
Department of Nutritional Medicine (180 a), University of Hohenheim, Stuttgart, Germany.
Kanuri
Giridhar
G
Wagnerberger
Sabine
S
Haub
Synia
S
Bischoff
Stephan C
SC
Bergheim
Ina
I
D000284:Administration, Oral; D000818:Animals; D004195:Disease Models, Animal; D004731:Endotoxins / Q000378:metabolism; D005234:Fatty Liver / Q000139:chemically induced* / Q000378:metabolism* / Q000473:pathology; D005260:Female; D005632:Fructose / Q000008:administration & dosage / Q000009:adverse effects* / Q000378:metabolism; D050838:Interferon Regulatory Factor-3 / Q000378:metabolism; D050839:Interferon Regulatory Factor-7 / Q000378:metabolism; D015227:Lipid Peroxidation / Q000502:physiology; D008099:Liver / Q000378:metabolism* / Q000473:pathology; D008297:Male; D051379:Mice; D008809:Mice, Inbred C3H; D053594:Myeloid Differentiation Factor 88 / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D054839:Retinol-Binding Proteins, Plasma / Q000378:metabolism; D051197:Toll-Like Receptor 4 / Q000235:genetics / Q000378:metabolism*; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000378:metabolism
D004731:Endotoxins; D050838:Interferon Regulatory Factor-3; D050839:Interferon Regulatory Factor-7; C494233:Irf3 protein, mouse; C494235:Irf7 protein, mouse; C507780:Myd88 protein, mouse; D053594:Myeloid Differentiation Factor 88; D012333:RNA, Messenger; C502487:Rbp4 protein, mouse; D017382:Reactive Oxygen Species; D054839:Retinol-Binding Proteins, Plasma; C493487:Tlr4 protein, mouse; D051197:Toll-Like Receptor 4; D014409:Tumor Necrosis Factor-alpha; D005632:Fructose; D052247:Nitric Oxide Synthase Type II; C496317:Nos2 protein, mouse; D051057:Proto-Oncogene Proteins c-akt