In 1980, Ludwig et al. first reported patients of steatohepatitis who lacked a history of excessive alcohol consumption but showed liver histology resembling alcoholic hepatitis and progression to cirrhosis of the liver accompanied by inflammation and fibrosis. The development of nonalcoholic steatohepatitis (NASH) is associated with obesity, diabetes mellitus, insulin resistance, and hyperlipidemia. However, the pathogenesis of NASH remains incomplete. A “multiple-hit” hypothesis for the pathogenesis of NASH based on an animal model has been proposed and remains a foundation for research in this field. We review the important dietary and genetic animal models and discuss the pathogenesis of NASH. 1. Introduction Although, until recently, fatty liver had been thought to take a benign clinical course, it is now known that nonalcoholic fatty liver disease (NAFLD) or NASH may progress to cirrhosis of the liver accompanied by inflammation and fibrosis [1]. It appears that the prevalence of simple steatosis is from 20% to 30% and in NASH from 2% to 3% in adults, and that NAFLD rarely leads to cirrhosis (3%) compared to NASH (up to 30%) [2]. Obesity, diabetes mellitus, insulin resistance, and hyperlipidemia are conditions frequently associated with NASH [3, 4]. The liver histology of NASH was confirmed by Brunt and colleagues and the NASH Clinical Research Network [5, 6]. The diagnostic standards include the extent of steatosis, hepatocellular inflammation, and fibrosis. In steatosis, microvesicular and macrovesicular lipid droplets can be revealed in the whole cytoplasm. In contrast to simple steatosis, in steatohepatitis (NASH) there is inflammation with the presence of steatosis, hepatocellular ballooning, and both lobular and portal inflammation with fibrosis. Moreover, pericellular fibrosis with collagen secreted from hepatic stellate cells is a typical formation that can spread to the portal area and lead to portal-portal and portal-central bridging fibrosis and cirrhosis [7]. The development and progression of NAFLD to NASH would occur via a “two-hit” process involving the interaction of genetic and environment factors [8, 9]. In brief, the progression from normal, healthy liver to steatohepatitis is a gradual process involving, first, the advance of obesity and insulin resistance and, next, inflammation [10]. However, this “two-hit” hypothesis remains controversial. In general, about 30% of patients in the spectrum of NAFLD develop NASH, while patients with only steatosis tend to remain stable over time [11]. To understand the cause of NASH, several
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