Background: While tumour necrosis factor α (TNF-α) appears to be associated with the development of non-alcoholic steatohepatitis (NASH), its precise role in the pathogenesis of NASH is not well understood.
Methods: Male mice deficient in both TNF receptors 1 (TNFR1) and 2 (TNFR2) (TNFRDKO mice) and wild-type mice were fed a methionine and choline deficient (MCD) diet or a control diet for eight weeks, maintaining isoenergetic intake.
Results: MCD dietary feeding of TNFRDKO mice for eight weeks resulted in attenuated liver steatosis and fibrosis compared with control wild-type mice. In the liver, the number of activated hepatic Kupffer cells recruited was significantly decreased in TNFRDKO mice after MCD dietary feeding. In addition, hepatic induction of TNF-α, vascular cell adhesion molecule 1, and intracellular adhesion molecule 1 was significantly suppressed in TNFRDKO mice. While in control animals MCD dietary feeding dramatically increased mRNA expression of tissue inhibitor of metalloproteinase 1 (TIMP-1) in both whole liver and hepatic stellate cells, concomitant with enhanced activation of hepatic stellate cells, both factors were significantly lower in TNFRDKO mice. In primary cultures, TNF-α administration enhanced TIMP-1 mRNA expression in activated hepatic stellate cells and suppressed apoptotic induction in activated hepatic stellate cells. Inhibition of TNF induced TIMP-1 upregulation by TIMP-1 specific siRNA reversed the apoptotic suppression seen in hepatic stellate cells.
Conclusions: Enhancement of the TNF-α/TNFR mediated signalling pathway via activation of Kupffer cells in an autocrine or paracrine manner may be critically involved in the pathogenesis of liver fibrosis in this NASH animal model.
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- TNF-α, tumour necrosis factor α
- NASH, non-alcoholic steatohepatitis
- ASH, alcoholic steatohepatitis
- TNFR, tumour necrosis factor receptor
- TNFRDKO mice, mice deficient in both TNFR1 and TNFR2
- MCD, methionine and choline deficient
- VCAM, vascular cell adhesion molecule
- ICAM, intracellular adhesion molecule
- PHB, prohibitin
- COX, cytochrome oxidase subunit
- TIMP, tissue inhibitor of metalloproteinase
- TGF-β, transforming growth factor β
- SREBP, sterol regulatory response element binding protein
- SCD, stearoyl-CoA desaturase
- FAS, fatty acid synthase
- HSD, hydroxysteroid dehydrogenase
- MTTP, microsomal triglyceride transfer protein
- TG, triglyceride
- ALT, alanine aminotransferase
- mAb, monoclonal antibody
- EMEM, Eagle’s minimum essential medium
- FBS, fetal bovine serum
- LPS, lipopolysaccharide
Published online first 20 September 2005
Conflict of interest: None declared.
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