Obesity is an inflammatory disorder characterized by heightened activity of the innate immune system. Innate immune activation is central to the development of obesity-related insulin resistance; it also plays an important role in obesity-related tissue damage, such as that seen in atherosclerosis. Recent research has implicated the innate immune system in the pathophysiology of obesity-related liver disease. This review summarizes how innate immune processes, occurring both within and outside the liver, cause not only insulin resistance but also end-organ damage in the form of nonalcoholic fatty liver disease. (HEPATOLOGY 2008;48:670-678.) O besity is the direct result of an imbalance between nutritional intake and energy expenditure, which leads to the storage of excess fuel as fat. Although adipose tissue represents the body's principal lipid storage reservoir, fat can accumulate ectopically in other organs such as muscle and liver. Regardless of its location (even in adipose tissue), excess fat can provoke abnormalities in tissue structure and function that result in end-organ damage. A growing body of evidence supports the concept that end-organ damage in obesity is an inflammatory condition. 1 Consequences of this systemic inflammation include type 2 diabetes mellitus, atherosclerosis, and nonalcoholic fatty liver disease (NAFLD). 1 With respect to the liver, immune pathways can adversely affect hepatic lipid metabolism and lead to serious outcomes such as hepatic injury, inflammation, and fibrosis. These processes are likely at play in the 72 million obese adults in the United States (www.cdc.gov/nchs/pressroom/07newsreleases/obesity.htm), 75% of whom have fatty livers. 2 The leukocytes, receptors, and soluble mediators involved in obesity-related inflammatory sequences are all part of the innate immune system. The evolutionary purpose of innate immunity is to defend against pathogens or foreign substances. In the setting of obesity, however, dietary fats or fatty acids may be perceived as foreign substances that modulate inflammation and its metabolic effects. Although a number of immune responses to fat can occur locally in target tissues, recent studies suggest a novel paradigm in which inflammation in adipose tissue is a master regulator of metabolic and immune dysfunction in other organs. In this context, an important question for the hepatologist is whether immune activation in adipose tissue is a prerequisite for the development of nonalcoholic steatohepatitis (NASH). Although data are currently incomplete, there is compelling evidence that adipose tissue inflammation exacerbates hepatic steatosis and can heighten innate inflammatory responses within the liver. 3,4 In this review, we will summarize evidence that innate immune pathways are activated in obesity and describe the involvement or proposed involvement of these pathways in the pathogenesis of NASH.
Fat-Induced Activation of Proinflammatory Pathways Causes Insulin Resistance
Fat can cause insulin resistance by prompting the activation of select serine kinases within a variety of insulinsensitive cells. Singly or in combination, these enzymes phosphorylate regulatory serine residues on the insulin receptor substrates IRS-1 and IRS-2, leading to the downmodulation of normal insulin-stimulated tyrosine phosphorylation and interfering with physiologic insulin