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As obesity creeps in epidemic proportions through increasingly inert and affluent “developed” societies, metabolic imbalance has become the commonest cause of liver disease. Fatty liver, although itself benign, predisposes the liver to NASH or non-alcoholic steatohepatitis, a chronic disorder characterised by steatosis, mixed cell type inflammation, focal hepatocyte degeneration, and perivenular or pericellular fibrosis.1 ,2 NASH is slowly progressive, occasionally resulting in cirrhosis with the potentially fatal complications of portal hypertension, liver failure, and hepatocellular carcinoma.2 ,3
Most cases of NASH appear to have a multifactorial aetiopathogenesis. The predisposing factors include obesity, type II diabetes, insulin resistance, hypertriglyceridaemia, and rapid weight loss, each of which can cause hepatic steatosis. The trigger that sets off injury and inflammation against this background of oxidisable fatty acid excess, and the mechanisms that perpetuate steatohepatitis and fibrogenesis are less clear.4 A focus of recent experimental studies has been on biochemical processes that reduce oxygen to reactive oxygen species (ROS); these can potentially damage tissues by the process of oxidative stress. Oxidative stress also increases expression of cellular adhesion molecules, and secretion of chemokines and cytokines, thereby initiating the recruitment of an hepatic inflammatory response.5 ,6
Weltman and colleagues demonstrated that cytochrome P450 (CYP)2E1 is over expressed in the livers of patients with NASH7 as well as in a model of steatohepatitis induced by feeding rats a high fat, methionine and choline deficient (MCD) diet.8Leclercq and colleagues then showed that CYP2E1 catalyses lipid peroxidation in the murine MCD dietary model,9contributing to profound oxidative stress. Alternatively, in Cyp2e1 nullizygous mice, CYP4A enzymes are upregulated and function as alternative catalysts of microsomal lipoperoxidation in experimental NASH.9 Other studies have implicated activation of the peroxisome proliferator activated receptor α (PPARα) …