Toll-like receptor-4 signaling and Kupffer cells play pivotal roles in the pathogenesis of non-alcoholic steatohepatitis

J Hepatol. 2007 Oct;47(4):571-9. doi: 10.1016/j.jhep.2007.04.019. Epub 2007 Jun 8.


Background/aims: Studies in animal models and humans suggest a link between endotoxemia and non-alcoholic steatohepatitis. Since Kupffer cells are responsible for clearing endotoxin and are activated via endotoxin interaction with Toll-like receptor 4 (TLR-4), we examined the relationship between hepatic TLR-4 expression and Kupffer cell content during the genesis of steatohepatitis.

Methods: Male C57BL/6, C3H/HouJ and TLR-4 mutant C3H/HeJ mice were fed control or methionine/choline-deficient diet (MCDD). In one group of C57BL/6 mice, Kupffer cells were depleted by weekly intraperitoneal injections of clodronate liposomes. After 3 weeks, serum ALT activity and portal endotoxin levels were measured. Real-time PCR was used to examine mRNA expression of TLR-4, TLR-2, CD14, MD-2, TGFbeta, TNFalpha, CD36, PPAR-alpha, liver fatty acid binding protein (L-FABP) and collagen alpha1.

Results: We observed histological evidence typical of steatohepatitis, portal endotoxemia and enhanced TLR-4 expression in wild type mice fed MCDD. In contrast, injury and lipid accumulation markers were significantly lower in TLR-4 mutant mice. Destruction of Kupffer cells with clodronate liposomes blunted histological evidence of steatohepatitis and prevented increases in TLR-4 expression.

Conclusions: These findings demonstrate the importance of TLR-4 signaling and underscore a direct link between TLR-4 and Kupffer cells in the pathogenesis of steatohepatitis.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Choline Deficiency
  • Clodronic Acid / pharmacology
  • Collagen Type I / deficiency
  • Diet
  • Endotoxemia / complications*
  • Endotoxemia / genetics
  • Fatty Liver / etiology*
  • Fatty Liver / pathology
  • Hepatitis, Animal / etiology*
  • Hepatitis, Animal / pathology
  • Kupffer Cells / drug effects
  • Kupffer Cells / physiology*
  • Lymphotoxin-alpha / deficiency
  • Methionine / deficiency
  • Mice
  • Mice, Mutant Strains
  • PPAR alpha / metabolism
  • Signal Transduction
  • Toll-Like Receptor 4 / genetics
  • Toll-Like Receptor 4 / physiology*
  • Triglycerides / analysis


  • Collagen Type I
  • Lymphotoxin-alpha
  • PPAR alpha
  • Toll-Like Receptor 4
  • Triglycerides
  • collagen type I, alpha 1 chain
  • Clodronic Acid
  • Methionine