**1. Introduction**

Non-alcoholic fatty liver disease (NAFLD), regarded as the 'hepatic manifestation of the metabolic syndrome', is now estimated to affect one billion individuals worldwide [1]. The definition of NAFLD is very simple such as the presence of at least 5% hepatic steatosis but excluding secondary hepatic fat accumulation of general causes, such as congenital hepatic disorders, chronic viral hepatitis, autoimmune hepatitis, excessive alcohol consumption, or long-term use of steatosis-inducing medications [2].

NASH is characterised by the development of histopathological changes in the liver that are nearly identical to those induced by excessive alcohol intake, but in the absence of alcohol abuse, the presence of macrovesicular steatosis and mixed inflammatory infiltrate associated with focal hepatocyte ballooning degeneration and varying amounts of Mallory's hyaline and glycogenated nuclei. However, liver biopsy still remains the "gold standard" for making a definitive diagnosis.

NASH is capable of progressing to cirrhosis and liver failure at the end of clinical course [3, 4]. Actually, NASH is forecasted to become the principal cause of advanced liver disease in developed countries [5] and the high-ranking indication for liver transplantation [4]. NAFLD has also been gradually acknowledged as an independent risk factor for the development of cardiovascular disease, type 2 diabetes mellitus (T2DM) and hepatocellular carcinoma [6, 7]. The factors that predispose patients to the development of steatohepatitis and fibrosis in NAFLD are not well elucidated, and effective treatment strategies are still lacking [8].

Day and James [9] initially proposed a 'two-hit' model to explain the progression of NAFLD. The 'first hit' constitutes the deposition of triglycerides in the cytoplasm of the hepatocytes. The disease does not progress unless additional cellular events occur (the 'second hit'), which can include oxidative stress, especially that arises from inflammatory cytokines, mitochondrial stress and insulin resistance. Autophagy may also play a notable role in the pathogenesis of NASH.

A new prospect explaining the pathogenesis of NASH was reported by Tilg and Moschen, called the 'multi-parallel hit' hypothesis recently [10]. This hypothesis, based on reports that cytokine-mediated stress and endoplasmic reticulum stress can induce steatosis as well as necroinflammation, suggests that multiple hits take a step together in the development of NASH. The progression of steatosis should, therefore, be regarded as a part of the liver's early 'adaptive' and 'purposive' response to some types of stress rather than as the first hit in the disease development. The close correlation between insulin resistance and iron level has been speculated and examined by many researchers. Even if secondary iron accumulation increases insulin resistance or vice versa, it remains still unclear. Oxidative stress may be the elusive 'second' hit of possibly multiple steps in the progression of steatosis to fibrosing steatohepatitis [11]. This type of response might be originated from and been modified by the activation of hepatic stellate cells (HSCs) [12].
