Molecular basis and mechanisms of progression of non-alcoholic steatohepatitis

Non-alcoholic steatohepatitis (NASH), a cause of cirrhosis and hepatocellular carcinoma, is characterized by fatty infiltration of the liver, inflammation, hepatocellular damage and fibrosis. Progress has been made in understanding the molecular and cellular mechanisms implicated in the pathogenesis of this condition, therefore, we here review recent developments regarding the basic mechanisms of NASH development. Accumulation of triglycerides in the hepatocytes is the result of increased inflow of free fatty acids and de novo lipogenesis. Steatosis leads to lipotoxicity, which causes apoptosis, necrosis, generation of oxidative stress and inflammation. The resulting chronic injury activates a fibrogenic response that leads eventually to end-stage liver disease. A better understanding of these mechanisms is crucial for the design of novel diagnostic and therapeutic strategies. Non-alcoholic steatohepatitis (NASH), a cause of cirrhosis and hepatocellular carcinoma, is characterized by fatty infiltration of the liver, inflammation, hepatocellular damage and fibrosis. Progress has been made in understanding the molecular and cellular mechanisms implicated in the pathogenesis of this condition, therefore, we here review recent developments regarding the basic mechanisms of NASH development. Accumulation of triglycerides in the hepatocytes is the result of increased inflow of free fatty acids and de novo lipogenesis. Steatosis leads to lipotoxicity, which causes apoptosis, necrosis, generation of oxidative stress and inflammation. The resulting chronic injury activates a fibrogenic response that leads eventually to end-stage liver disease. A better understanding of these mechanisms is crucial for the design of novel diagnostic and therapeutic strategies. cytokines produced predominantly at the level of adipose tissue. Their action is both local (autocrine or paracrine) and distant (hormonal). Adipokines produced by visceral fat target the liver primarily through the portal circulation. endogenous synthesis of FFAs within the liver. these surround the sinusoids in the normal liver, where they have a ‘quiescent’ state. After injury, these cells ‘activate’ and acquire features that are relevant for the development of fibrogenesis. fat accumulation in the liver of subjects with absent or low (<20–30 g/day) alcohol consumption. the histological picture observed in a subset of patients with NAFLD. Besides fatty infiltration, variable degrees of hepatocyte damage, inflammation and fibrosis are present. molecules belonging to the family of nuclear hormone receptors. Regulate transcription on binding with ligands. Transcriptional activity is modulated by a wide number of co-activators and co-repressors. highly reactive molecules, the levels of which can increase dramatically during different types of stress, resulting in damage to cell structures. This cumulates into a situation defined as oxidative stress. a class of antidiabetic drugs that function as PPAR-γ ligands. fat accumulation inside the abdominal cavity, localized mostly in the omentum. Products of this type of adipose tissue are drained by the portal circulation.