The implication of the anti-inflammatory signaling through IL-4, IL-13 and STAT6 in metabolic disease has never been reported. Different studies have evaluated the implication of IL-4 or IL-13 in the incidence of liver disease and these cytokines seems to have a deleterious effect on liver T cell mediated hepatotoxicity. For example a study showed that IL-4 and deficient mice was protected from Concanavalin A induced hepatitis and IL-13 knock-out mice were protected from acetaminophen overload (149).
Finally overexpression of IL-4 has been recently reported to promote hepatocyte apoptosis. These examples suggest a deleterious effect of IL-4 and IL-13 in certain liver function. Similarly, by suppressing STAT6 anti-inflammatory effect, Lentsch (et al.) observed an augmentation of pro-inflammatory cytokines production leading to leukocytes accumulation and significant hepato-cellular injury (150). By contrast, STAT6 is protective against ischemia/reperfusion induced injury which leads to cellular damage by inducing fluctuations in oxygen, nutrition and energy availability (151-153). These disorders are also a characteristic feature of metabolic disturbances, most notably glucose intolerance and insulin resistance. The relationship between hypoxia, metabolism and liver injury is highlighted by studies demonstrating that intermittent hypoxia induces alterations in lipid homeostasis and predisposes to liver injury (151-153). Notably, STAT6 is not only expressed in immune related cells but also in different other cell types, raising the possibility of a broader physiological significance from previously supposed.
Indeed, STAT6 has been shown to be involved in adipocyte differentiation, kidney epithelial cell mechanosensation, regulation of apoptosis in human hepatoma cells as well as inflammatory reaction in lung epithelial cells (154-156). Therefore, STAT6-deficient mice, in addition to impaired immune functionality display severe and multiple disorders (157).
In addition to its protective role in ischemia/reperfusion, STAT6 has been shown to be involved in atherosclerosis. Indeed, STAT6 KO mice develop more severe aortic wall lipid accumulation upon high fat diet feeding and, in humans, it was identified as one of the three up-regulated genes in atherosclerotic coronary plaques (158, 159).
Recently, STAT6 was reported to play a role in fatty acid oxidation in macrophages. This protein modulates lipid metabolism and cellular proliferation in alternatively activated macrophages (156, 160). STAT6 is intimately involved in this process, contributing to the switch between glycolytic and lypolytic metabolism. Interestingly, STAT6 provide a counterbalance to the transcription factor Hypoxia Induced Factor α (HIFα) allowing resulting in an increase in lypolytic activity and allowing wound healing (Figure 17).
Figure 17: STAT6 activation can lead to fatty acid oxidation in the macrophage from Lacy-Hulbert (et al.) (161).
Hepatocyte are master regulators of glucose and lipid metabolism and are known to express STAT6 (154). Despite of the growing evidence of the involvement of STAT6 in non-immune cell function the role of STAT6 has never been evaluated in the context of the development of metabolic diseases and their related complications. To explore this potential new function, the liver proteomes of wild type and STAT6 knock-out mice were compared using two different quantitative techniques, namely 2D-PAGE gel electrophoresis and a combination of 2D nanoscale LC-MS/MS with iTRAQ labeling technique. These techniques will be reviewed in the next chapter.
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