Gastroenterology

Gastroenterology

Volume 131, Issue 3, September 2006, Pages 934-945
Gastroenterology

Special reports and review
Nonalcoholic Fatty Liver Disease: Cytokine-Adipokine Interplay and Regulation of Insulin Resistance

https://doi.org/10.1053/j.gastro.2006.05.054Get rights and content

Nonalcoholic fatty liver disease (NAFLD), the major reason for abnormal liver function in the Western world, is associated with obesity and diabetes and is characterized by insulin resistance (IR). IR is regulated by mediators released from cells of the immune system or adipocytes and proinflammatory cytokines such as tumor necrosis factor-α (TNFα). The importance of TNFα in human and animal fatty liver diseases, both caused by genetic manipulation and overnutrition, has been shown convincingly. Furthermore, neutralization of TNFα activity improves IR and fatty liver disease in animals. Adiponectin is a potent TNFα-neutralizing and anti-inflammatory adipokine 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 exerted both by suppressing TNFα synthesis and by induction of anti-inflammatory cytokines such as interleukin-10 or interleukin-1–receptor antagonist. Therefore, the balance between various mediators, either derived from the immune system or adipose tissue, appears to play an important role in hepatic and systemic insulin action and in the development of fatty liver disease.

Section snippets

Cytokines in NAFLD

Identification of the mechanisms that cause and mediate obesity-related fatty liver disease are awaited and progress in the past few years has been substantial.6, 7 Cytokines are critically involved in the physiology of a healthy liver and in the pathophysiology of many acute and chronic liver diseases. These mediators are released by almost all cell types in the liver and play a fundamental role in liver function and regeneration. Cytokines are key mediators of hepatic inflammation, liver cell

Adiponectin, the Key TNFα-Neutralizing Adipocytokine, and Its Role in Inflammation and NAFLD

Adipose tissue and its metabolic products recently have gained great interest. Various products of the fat tissue have been characterized including not only cytokines such as TNFα or IL-6, but also the so-called adipo(cyto)kines including leptin, adiponectin, and visfatin.8 Adiponectin, the predominant protein synthesized by adipocytes, circulates in rather high concentrations and shows a wide spectrum of biological activities.

Adiponectin is secreted predominantly from adipose tissue and shares

Hepatic IR and Underlying Mechanisms

The first link between obesity, increase in the expression of a proinflammatory cytokine, namely TNFα, and insulin action came from a study more than 13 years ago.95 These findings led to the concept of inflammation in obesity and showed that adipocytes express TNFα. In these studies, expression of this cytokine in obese animals (fa/fa rat and ob/ob mouse) has been increased and shown to regulate insulin action.95 Further evidence supporting a key role for TNFα in IR came from studies published

Conclusions

NAFLD has emerged as a major cause of abnormal liver function tests worldwide and is considered an integral part of the metabolic syndrome. Accumulating insights should help clinicians to consider this diagnosis even when patients present without other clinical features of the metabolic syndrome, thereby allowing early identification of this syndrome. Cytokines and adipokines seem to play a major role at various stages of NAFLDs and improvement of understanding in the past few years has clearly

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    Supported by the Christian Doppler Society and a grant from the Austrian Science Foundation (P17447), National Institutes of Health USA (DK52539 and DK64360), and the American Diabetes Association.

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