Differential liver sensitization to toll-like receptor pathways in mice with alcoholic fatty liver

Thierry Gustot, Arnaud Lemmers, Christophe Moreno, Nathalie Nagy, Eric Quertinmont, Charles Nicaise, Denis Franchimont, Hubert Louis, Jacques Devière, Olivier Le Moine

Research output: Contribution to journalArticle

Abstract

Gut-derived, endotoxin-mediated hepatocellular damage has been postulated to play a crucial role in the pathogenesis of alcohol-induced liver injury in rodents. Endotoxins induce production of tumor necrosis factor alpha (TNF-alpha) by Kupffer cells via Toll-like receptor (TLR) 4 and contribute to liver injury. This study addressed the contribution of other TLRs and ligands to alcoholic fatty liver. C57Bl6/J mice were fed a modified Lieber-DeCarli diet. Serum aminotransferase measurements, histological analysis, and quantification of liver TNF-alpha and TLR1-9 messenger RNA (mRNA) were performed. The effect of TLR ligands on liver injury was assessed in vivo. Neomycin and metronidazole or diphenyleneiodonium sulfate (DPI) were administered to evaluate the role of gut bacteria and NADPH oxidase activity, respectively, in hepatic TLR expression. Enteral ethanol (EtOH) exposure induced steatosis and increased liver weight, aminotransferase levels, and expression of TLR1, 2, 4, 6, 7, 8, and 9 liver mRNA. Injection of lipoteichoic acid, peptidoglycan (PGN), lipopolysaccharide (LPS), loxoribine, and oligonudeotide containing CpG (ISS-ODN) increased TNF-alpha mRNA expression more in the livers of EtOH-fed mice than in control mice. PGN, LPS, flagellin, and ISS-ODN induced liver inflammatory infiltrate in EtOH-fed mice but not control mice. Addition of antibiotics reduced the severity of alcoholic fatty liver without affecting TLR expression, whereas daily DPI injections reduced the EtOH-mediated upregulation of TLR2, 4, 6, and 9 mRNA. In conclusion, EtOH-fed mice exhibited an oxidative stress dependent on upregulation of multiple TLRs in the liver and are sensitive to liver inflammation induced by multiple bacterial products recognized by TLRs.
Original languageEnglish
Pages (from-to)989-1000
Number of pages12
JournalHepatology
Volume43
Issue number5
DOIs
Publication statusPublished - May 2006

Fingerprint

Alcoholic Fatty Liver
Toll-Like Receptors
Liver
Messenger RNA
Peptidoglycan
Tumor Necrosis Factor-alpha
Transaminases
Endotoxins
Sulfates
Lipopolysaccharides
Wounds and Injuries
Up-Regulation
Ligands
Flagellin
Toll-Like Receptor 4
Injections
Kupffer Cells
Neomycin
NADPH Oxidase
Metronidazole

Keywords

  • Animals
  • Ethanol
  • Fatty Liver, Alcoholic
  • Female
  • Liver
  • Mice
  • Mice, Inbred C57BL
  • NADP
  • Oxidation-Reduction
  • RNA, Messenger
  • Signal Transduction
  • Toll-Like Receptors

Cite this

Gustot, T., Lemmers, A., Moreno, C., Nagy, N., Quertinmont, E., Nicaise, C., ... Le Moine, O. (2006). Differential liver sensitization to toll-like receptor pathways in mice with alcoholic fatty liver. Hepatology, 43(5), 989-1000. https://doi.org/10.1002/hep.21138
Gustot, Thierry ; Lemmers, Arnaud ; Moreno, Christophe ; Nagy, Nathalie ; Quertinmont, Eric ; Nicaise, Charles ; Franchimont, Denis ; Louis, Hubert ; Devière, Jacques ; Le Moine, Olivier. / Differential liver sensitization to toll-like receptor pathways in mice with alcoholic fatty liver. In: Hepatology. 2006 ; Vol. 43, No. 5. pp. 989-1000.
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Gustot, T, Lemmers, A, Moreno, C, Nagy, N, Quertinmont, E, Nicaise, C, Franchimont, D, Louis, H, Devière, J & Le Moine, O 2006, 'Differential liver sensitization to toll-like receptor pathways in mice with alcoholic fatty liver', Hepatology, vol. 43, no. 5, pp. 989-1000. https://doi.org/10.1002/hep.21138

Differential liver sensitization to toll-like receptor pathways in mice with alcoholic fatty liver. / Gustot, Thierry; Lemmers, Arnaud; Moreno, Christophe; Nagy, Nathalie; Quertinmont, Eric; Nicaise, Charles; Franchimont, Denis; Louis, Hubert; Devière, Jacques; Le Moine, Olivier.

In: Hepatology, Vol. 43, No. 5, 05.2006, p. 989-1000.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Differential liver sensitization to toll-like receptor pathways in mice with alcoholic fatty liver

AU - Gustot, Thierry

AU - Lemmers, Arnaud

AU - Moreno, Christophe

AU - Nagy, Nathalie

AU - Quertinmont, Eric

AU - Nicaise, Charles

AU - Franchimont, Denis

AU - Louis, Hubert

AU - Devière, Jacques

AU - Le Moine, Olivier

PY - 2006/5

Y1 - 2006/5

N2 - Gut-derived, endotoxin-mediated hepatocellular damage has been postulated to play a crucial role in the pathogenesis of alcohol-induced liver injury in rodents. Endotoxins induce production of tumor necrosis factor alpha (TNF-alpha) by Kupffer cells via Toll-like receptor (TLR) 4 and contribute to liver injury. This study addressed the contribution of other TLRs and ligands to alcoholic fatty liver. C57Bl6/J mice were fed a modified Lieber-DeCarli diet. Serum aminotransferase measurements, histological analysis, and quantification of liver TNF-alpha and TLR1-9 messenger RNA (mRNA) were performed. The effect of TLR ligands on liver injury was assessed in vivo. Neomycin and metronidazole or diphenyleneiodonium sulfate (DPI) were administered to evaluate the role of gut bacteria and NADPH oxidase activity, respectively, in hepatic TLR expression. Enteral ethanol (EtOH) exposure induced steatosis and increased liver weight, aminotransferase levels, and expression of TLR1, 2, 4, 6, 7, 8, and 9 liver mRNA. Injection of lipoteichoic acid, peptidoglycan (PGN), lipopolysaccharide (LPS), loxoribine, and oligonudeotide containing CpG (ISS-ODN) increased TNF-alpha mRNA expression more in the livers of EtOH-fed mice than in control mice. PGN, LPS, flagellin, and ISS-ODN induced liver inflammatory infiltrate in EtOH-fed mice but not control mice. Addition of antibiotics reduced the severity of alcoholic fatty liver without affecting TLR expression, whereas daily DPI injections reduced the EtOH-mediated upregulation of TLR2, 4, 6, and 9 mRNA. In conclusion, EtOH-fed mice exhibited an oxidative stress dependent on upregulation of multiple TLRs in the liver and are sensitive to liver inflammation induced by multiple bacterial products recognized by TLRs.

AB - Gut-derived, endotoxin-mediated hepatocellular damage has been postulated to play a crucial role in the pathogenesis of alcohol-induced liver injury in rodents. Endotoxins induce production of tumor necrosis factor alpha (TNF-alpha) by Kupffer cells via Toll-like receptor (TLR) 4 and contribute to liver injury. This study addressed the contribution of other TLRs and ligands to alcoholic fatty liver. C57Bl6/J mice were fed a modified Lieber-DeCarli diet. Serum aminotransferase measurements, histological analysis, and quantification of liver TNF-alpha and TLR1-9 messenger RNA (mRNA) were performed. The effect of TLR ligands on liver injury was assessed in vivo. Neomycin and metronidazole or diphenyleneiodonium sulfate (DPI) were administered to evaluate the role of gut bacteria and NADPH oxidase activity, respectively, in hepatic TLR expression. Enteral ethanol (EtOH) exposure induced steatosis and increased liver weight, aminotransferase levels, and expression of TLR1, 2, 4, 6, 7, 8, and 9 liver mRNA. Injection of lipoteichoic acid, peptidoglycan (PGN), lipopolysaccharide (LPS), loxoribine, and oligonudeotide containing CpG (ISS-ODN) increased TNF-alpha mRNA expression more in the livers of EtOH-fed mice than in control mice. PGN, LPS, flagellin, and ISS-ODN induced liver inflammatory infiltrate in EtOH-fed mice but not control mice. Addition of antibiotics reduced the severity of alcoholic fatty liver without affecting TLR expression, whereas daily DPI injections reduced the EtOH-mediated upregulation of TLR2, 4, 6, and 9 mRNA. In conclusion, EtOH-fed mice exhibited an oxidative stress dependent on upregulation of multiple TLRs in the liver and are sensitive to liver inflammation induced by multiple bacterial products recognized by TLRs.

KW - Animals

KW - Ethanol

KW - Fatty Liver, Alcoholic

KW - Female

KW - Liver

KW - Mice

KW - Mice, Inbred C57BL

KW - NADP

KW - Oxidation-Reduction

KW - RNA, Messenger

KW - Signal Transduction

KW - Toll-Like Receptors

U2 - 10.1002/hep.21138

DO - 10.1002/hep.21138

M3 - Article

C2 - 16628628

VL - 43

SP - 989

EP - 1000

JO - Hepatology

JF - Hepatology

SN - 0270-9139

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ER -