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Volume 70 - 2007 - Fasc.1 - Georges Brohée Prize

Pathogenesis of steatohepatitis : insights from the study of animal models

Non-alcoholic steatohepatitis (NASH) is a disease of expanded clinical importance. Its pathogenesis remains poorly understood. Tools to identify patients at risk and targeted treatments are lack- ing. The aim of this work was to analyse potential pathogenic mech- anisms for inflammatory recruitment and fibrogenesis in NASH, using animal models. We demonstrated that oxidative stress, invariably associated with NASH, is a primary and necessary event for disease progres- sion. Inhibition of stress-activated transcription factor NF-kB pre- vents NASH. NF-kB therefore appears as a pathogenic link between oxidative stress and NASH. Increased lipid b-oxidation in NASH could generate oxidative stress. We used a potent inducer of PPAR-alpha to stimulate b-oxi- dation in a model of steatohepatitis. Such treatment induced a complete clearance of steatosis together with a significant reduc- tion of oxidative stress and oxidative injuries and prevention of inflammation and fibrosis. Thus in a situation of steatosis, stimulation of lipid combustion depletes the substrates for lipid peroxidation and thereby decreases oxidative stress. This effect is sufficiently powerful to prevent the development of steatohepatitis. We demonstrated that leptin is a pro-fibrogenic adipocytokine and is implicated in the regulation of liver regeneration. Leptin plays this crucial physiological role in hepatic wound healing by controlling the production and the activation of cytokines. The insulin sensitising drugs thiazolidinediones have anti- inflammatory and anti-fibrotic properties in rats. We demonstrat- ed that such drugs are poorly effective in the treatment of pre- established hepatic fibrosis in rats and unable to prevent fibroge- nesis in vitro as well as in vivo in mice. Direct anti-fibrotic effect of such substances remains to be demonstrated in humans. In conclusion, our work demonstrates the importance of oxida- tive stress in the pathogenesis of NASH, the role of intrahepatic lipid overload and underlies the links between adipose tissue and the liver. (Acta gastroenterol. belg., 2007, 70, 25-31).