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 lacking. The aim of this work was to analyse potential pathogenic mechanisms 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 progression. Inhibition of stress-activated transcription factor NF-chiB prevents NASH. NF-chiB therefore appears as a pathogenic link between oxidative stress and NASH. Increased lipid beta-oxidation in NASH could generate oxidative stress. We used a potent inducer of PPAR-alpha to stimulate beta-oxidation in a model of steatohepatitis. Such treatment induced a complete clearance of steatosis together with a significant reduction 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 antiinflammatory and anti-fibrotic properties in rats. We demonstrated that such drugs are poorly effective in the treatment of preestablished hepatic fibrosis in rats and unable to prevent fibrogenesis 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 oxidative stress in the pathogenesis of NASH, the role of intrahepatic lipid overload and underlies the links between adipose tissue and the liver.