An integrated view of liver injury and disease progression in nonalcoholic steatohepatitis.

Nonalcoholic fatty liver disease (NAFLD) is rapidly becoming the most common cause of chronic liver disease globally. NAFLD represents a host of pathophysiologic mechanisms that culminate in the accumulation of fat, in a predominantly macrovesicular pattern, in the liver along with varying degrees of inflammation, hepatocellular injury, apoptosis and fibrosis. The most common mechanism for the development of NAFLD is insulin resistance. Insulin resistance is commonly associated with obesity, although it can develop in individuals who do not have obesity. A consequence of insulin resistance is increased peripheral lipolysis and increased delivery of free fatty acids to the liver. The concept of lipotoxicity emerged as the mechanisms by which fatty acids produce cell injury, promote apoptosis and activate inflammatory pathways were elucidated. While much work has been done mainly in cell culture models, the free fatty acid concentration in the liver is not significantly changed in NAFLD. Recently, the focus has shifted to alterations in other lipid metabolic pathways that appear to play an important role in the genesis of nonalcoholic steatohepatitis, the aggressive form of NAFLD. The innate immune system and the intestinal microbiota have been implicated in the development of NAFLD. These mechanisms are reviewed in this article.