|WANG, AN-JIANG - University Of Maryland|
|YANG, ZHONGHAN - University Of Maryland|
|GRINCHUK, VICTORIA - University Of Maryland|
|QIN, BOLIN - University Of Maryland|
|LU, N - University Of Maryland|
|WANG, DUAN - University Of Maryland|
|WANG, HONGBING - University Of Maryland|
|RAMALINGAM, T - National Instiute Of Allergy And Infectious Diseases (NIAID, NIH)|
|WYNN, THOMAS - National Instiute Of Allergy And Infectious Diseases (NIAID, NIH)|
|SHEA-DONOHUE, TEREZ - University Of Maryland|
|ZHAO, AIPING - University Of Maryland|
Submitted to: Journal of Immunology
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 9/30/2015
Publication Date: 11/15/2015
Citation: Wang, A., Yang, Z., Grinchuk, V., Smith, A.D., Qin, B., Lu, N., Wang, D., Wang, H., Ramalingam, T.R., Wynn, T.A., Urban Jr, J.F., Shea-Donohue, T., Zhao, A. 2015. IL-25 or IL-17E protects against high-fat diet-induced hepatic steatosis in mice dependent upon IL-13 activation of STAT6. Journal of Immunology. 195(10): 4771-4780. doi:10.4049/jimmunol.1500337.
Interpretive Summary: There is growing interest in the mechanisms that link nutrition, immune function, and metabolism. Non-alcoholic fatty liver disease (NAFLD) represents a spectrum of liver disease linked to obesity. Major factors that contribute to the development of NAFLD include eating a high fat/high calorie diet, type 2 diabetes, and lipid accumulation. The prevalence of NAFLD has been increasing steadily in recent decades with a current estimate of 20% of all adults being affected. The hallmark of NAFLD is steatosis characterized by lipid droplet accumulation in liver cells called hepatocytes. Excessive lipid accumulation/storage in the liver arises from an imbalance between lipid acquisition and disposal. Inflammation is a core component linking obesity and associated metabolic diseases including NAFLD through the release of pro-inflammatory molecules induced by immune activation. The present study was designed to investigate: (i) the effects of treatment of obesity-associated hepatic steatosis in mice with an immune cytokine called IL-25 known to reduce pro-inflammatory cytokines; (ii) the molecular mechanisms of IL-25 regulation of lipid accumulation/storage; (iii) the contribution of the interaction between IL-25 and the signaling IL-13-STAT6 pathway; and (iv) the impact of IL-25 deficiency on expression of hepatic steatosis. The results of the study demonstrated that IL-25 is important in maintaining lipid metabolic homeostasis in the liver. Injection of IL-25 promoted development of specialized cells in the liver called alternative activation of macrophage that inhibited inflammatory molecules and decreased proteins associated with lipid droplets in the liver cells. These effects led to a significantly decreased lipid accumulation in the liver in mice fed a high fat diet. These results implicate IL-25 and downstream signaling pathways as potential therapeutic targets for control of human hepatic steatosis and associated pathologies.
Technical Abstract: IL-25 is a member of IL-17 cytokine family and has immune-modulating activities. The role of IL-25 in maintaining lipid metabolic homeostasis remains unknown. Here, we investigated the effects of exogenous IL-25 or deficiency of IL-25 on lipid accumulation in the liver. Mice were injected with IL-25 to test for amelioration of hepatic steatosis induced by feeding a high-fat diet (HFD). The underlying molecular mechanisms were investigated by analyzing expression of cytokines, key enzymes for lipid metabolic pathways, activation markers for Kupffer cells, and lipid droplet (LD)-associated proteins. Mice genetically deficient in STAT6 or IL-13 were used to determine contribution of specific effector molecule and signaling pathway. Role of IL-25 was further investigated using mice deficient in IL-25. HFD-induced hepatic steatosis was accompanied by increased LD-associated proteins but decreased IL-25 expression in the liver. Administration of IL-25 to HFD-fed wild-type mice led to significant improvement in hepatic steatosis. This effect was associated with increased expression of type 2 cytokines, development of alternatively-activated Kupffer cells, as well as decreased expression of LD-associated proteins in the liver. In contrast, administration of IL-25 to HFD-fed mice deficient in STAT6 or IL-13 had no effects on hepatic steatosis or expression of the genes that were altered in HFD-fed WT mice. In addition, direct stimulation of primary hepatocytes with IL-13, but not IL-25, resulted in down-regulation of LD-associated proteins. Finally, mice deficient in IL-25 had exacerbated hepatic steatosis when fed the HFD, as compared to the respective WT mice. Conclusions: Dysregulated IL-25 expression contributes to lipid accumulation, while exogenous IL-25 protects against hepatic steatosis through IL-13 activation of STAT6. IL-25 and IL-13 are potential therapeutic agents for hepatic steatosis and associated pathologies.