Deficiency in myeloid differentiation factor-2 and toll-like receptor 4 expression attenuates nonalcoholic steatohepatitis and fibrosis in mice

Timea Csak, Arumugam Velayudham, I. Hritz, Jan Petrasek, Ivan Levin, Dora Lippai, Donna Catalano, Pranoti Mandrekar, Angela Dolganiuc, Evelyn Kurt-Jones, G. Szabó

Research output: Contribution to journalArticle

124 Citations (Scopus)

Abstract

Toll-like receptor 4 (TLR4) and its coreceptor, myeloid differentiation factor-2 (MD-2), are key in recognition of lipopolysaccharide (LPS) and activation of proinflammatory pathways. Here we tested the hypothesis that TLR4 and its coreceptor MD-2 play a central role in nonalcoholic steatohepatitis (NASH) and liver fibrosis in nonalcoholic fatty liver disease. Mice of control genotypes and those deficient in MD-2 or TLR4 [knockout (KO)] received methionine choline-deficient (MCD) or methionine choline-supplemented (MCS) diet. In mice of control genotypes, MCD diet resulted in NASH, liver triglycerides accumulation, and increased thiobarbituric acid reactive substances, a marker of lipid peroxidation, compared with MCS diet. These features of NASH were significantly attenuated in MD-2 KO and TLR4 KO mice. Serum alanine aminotransferase, an indicator of liver injury, was increased in MCD diet-fed genotype controls but was attenuated in MD-2 KO and TLR4 KO mice. Inflammatory activation, indicated by serum TNF-α and nictoinamide adenine dinucleotide phosphate oxidase complex mRNA expression and activation, was significantly lower in MCD diet-fed MD-2 KO and TLR4 KO compared with corresponding genotype control mice. Markers of liver fibrosis [collagen by Sirius red and α-smooth muscle actin (SMA) staining, procollagen-I, transforming growth factor-β1, α-SMA, matrix metalloproteinase- 2, and tissue inhibitor of matrix metalloproteinase-1 mRNA] were attenuated in MD-2 and TLR4 KO compared with their control genotype counterparts. In conclusion, our results demonstrate a novel, critical role for LPS recognition complex, including MD-2 and TLR4, through NADPH activation in liver steatosis, and fibrosis in a NASH model in mice.

Original languageEnglish
Pages (from-to)433-441
Number of pages9
JournalAmerican Journal of Physiology - Gastrointestinal and Liver Physiology
Volume300
Issue number3
DOIs
Publication statusPublished - Mar 2011

Fingerprint

Toll-Like Receptor 4
Fibrosis
Choline
Methionine
Genotype
Diet
Liver Cirrhosis
Knockout Mice
Smooth Muscle
Lipopolysaccharides
Actins
Procollagen
Messenger RNA
Matrix Metalloproteinase 1
Tissue Inhibitor of Metalloproteinase-1
Matrix Metalloproteinase Inhibitors
Thiobarbituric Acid Reactive Substances
Non-alcoholic Fatty Liver Disease
Liver
Matrix Metalloproteinase 2

Keywords

  • α-smooth muscle actin
  • Endotoxin
  • Fatty liver
  • Inflammation
  • Nictoinamide adenine dinucleotide phosphate

ASJC Scopus subject areas

  • Gastroenterology
  • Physiology (medical)
  • Physiology
  • Hepatology

Cite this

Deficiency in myeloid differentiation factor-2 and toll-like receptor 4 expression attenuates nonalcoholic steatohepatitis and fibrosis in mice. / Csak, Timea; Velayudham, Arumugam; Hritz, I.; Petrasek, Jan; Levin, Ivan; Lippai, Dora; Catalano, Donna; Mandrekar, Pranoti; Dolganiuc, Angela; Kurt-Jones, Evelyn; Szabó, G.

In: American Journal of Physiology - Gastrointestinal and Liver Physiology, Vol. 300, No. 3, 03.2011, p. 433-441.

Research output: Contribution to journalArticle

Csak, Timea ; Velayudham, Arumugam ; Hritz, I. ; Petrasek, Jan ; Levin, Ivan ; Lippai, Dora ; Catalano, Donna ; Mandrekar, Pranoti ; Dolganiuc, Angela ; Kurt-Jones, Evelyn ; Szabó, G. / Deficiency in myeloid differentiation factor-2 and toll-like receptor 4 expression attenuates nonalcoholic steatohepatitis and fibrosis in mice. In: American Journal of Physiology - Gastrointestinal and Liver Physiology. 2011 ; Vol. 300, No. 3. pp. 433-441.
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AU - Levin, Ivan

AU - Lippai, Dora

AU - Catalano, Donna

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