Nonalcoholic fatty liver disease (NAFLD) is the most common form of liver pathologies and is associated with obesity and the metabolic syndrome, which represents a range of fatty liver diseases associated with an increased risk of type 2 diabetes. Molecular mechanisms underlying how to make transition from simple fatty liver to nonalcoholic steatohepatitis (NASH) are not well understood. However, accumulating evidence indicates that deregulation of the phosphatidylinositol 3-kinase (PI3K)/AKT pathway in hepatocytes is a common molecular event associated with metabolic dysfunctions including obesity, metabolic syndrome, and the NAFLD. A tumor suppressor PTEN negatively regulates the PI3K/AKT pathways through its lipid phosphatase activity. Molecular studies in the NAFLD support a key role for PTEN in hepatic insulin sensitivity and the development of steatosis, steatohepatitis, and fibrosis. We review recent studies on the features of the PTEN and the PI3K/AKT pathway and discuss the protein functions in the signaling pathways involved in the NAFLD. The molecular mechanisms contributing to the diseases are the subject of considerable investigation, as a better understanding of the pathogenesis will lead to novel therapies for a condition. 1. Introduction Nonalcoholic fatty liver diseases (NAFLD) represent a hepatic metabolic syndrome, which is the common broad-spectrum liver disease, and it is becoming a worldwide health problem. NAFLD ranges from nonalcoholic fatty liver to nonalcoholic steatohepatitis (NASH), which often precedes liver fibrosis, cirrhosis, and hepatocellular carcinoma. NAFLD is also associated with obesity, type 2-diabetes, and metabolic syndrome [1–5]. Insulin resistance appears to induce the fat accumulation in hepatocytes and renders the liver more susceptible to diseases [6]. In addition, reactive oxygen species (ROS), endotoxins, and inflammatory cytokines result in the disease development [7]. It is also well known that several stressors like cigarette smoke, pollutants, diabetes, hypertension, and hypercholesterolemia are all risk factors to the disease [8, 9]. The hepatic insulin resistance state of fatty liver infiltration is characterized by increased free fatty acids (FFAs), which causes lipotoxicity, impairs endothelium-dependent vasodilatation, and increases oxidative stresses. Additional metabolic risk factors include leptin, adiponectin, and plasminogen activator inhibitor-1 (PAI-1), which together lead to increased oxidative stress and endothelial dysfunction [10]. Inflammation and fibrogenesis are closely related and
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