The Role of Cytokines in Non-Alcoholic Fatty Liver Disease

Non-alcoholic fatty liver disease (NAFLD) is commonly associated with obesity and diabetes, and is characterized by insulin resistance (IR). Cytokines and adipocytokines (i.e. mediators mainly derived from adipose tissue) play a major role in the orchestration of inflammatory processes throughout the body. In addition, many of these mediators are able to regulate very diverse functions including inflammatory, immune and metabolic processes such as IR. The pro-inflammatory cytokines tumor necrosis factor-alpha (TNF-alpha) and interleukin-6 (IL-6) are critically involved in the pathophysiology of various aspects of human NAFLD. The importance of TNF-alpha in human and animal fatty liver diseases, both due to genetic manipulation and overnutrition, has been demonstrated. Furthermore, neutralization of TNF-alpha activity improves IR and fatty liver disease in animals. IL-6 is derived from many cells throughout the body including adipocytes. Serum levels of this cytokine correlate remarkably well with the presence of IR, and adipose tissue-derived IL-6 has been shown to regulate hepatic IR via upregulation of SOCS3. Adiponectin is a potent TNF-alpha-neutralizing and anti-inflammatory adipocytokine, and in vitro and experimental animal studies have proven the importance of this mediator in counteracting inflammation and IR. Anti-inflammatory effects of adiponectin are mediated via suppression of TNF-alpha synthesis as well as induction of anti-inflammatory cytokines such as IL-10 or IL-1 receptor antagonist. Therefore, the balance between pro- and anti-inflammatory acting cytokines/adipocytokines appears to play a key role in hepatic and systemic insulin action, and they are supposed to have important functions in the development of NAFLD.