title: IL-25 or IL-17E Protects against High-Fat Diet-Induced Hepatic Steatosis in Mice Dependent upon IL-13 Activation of STAT6.
abstract: IL-25 or IL-17E 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. We investigated the effects of exogenous IL-25 or deficiency of IL-25 on hepatic lipid accumulation. IL-25 expression was examined in paraffin-embedded tissue sections of liver from patients or in the livers from mice. Mouse model of steatosis was induced by feeding a high-fat diet (HFD). Extent of steatosis as well as expression of cytokines, key enzymes for lipid metabolic pathways, markers for Kupffer cells/macrophages, and lipid droplet (LD) proteins, were analyzed. Our results show that hepatic steatosis in mice was accompanied by increased LD proteins, but decreased IL-25 in the liver. Decreased hepatic IL-25 was also observed in patients with fatty liver. Administration of IL-25 to HFD-fed wild-type mice led to a significant improvement in hepatic steatosis. This effect was associated with increased expression of IL-13, development of alternatively activated Kupffer cells/macrophages, and decreased expression of LD proteins in the liver. In contrast, administration of IL-25 to HFD-fed mice deficient in STAT6 or IL-13 had no effects. In addition, stimulation of primary hepatocytes with IL-13, but not IL-25, resulted in downregulation of LD proteins. Finally, mice deficient in IL-25 had exacerbated hepatic lipid accumulation when fed the HFD. These data demonstrate that dysregulated IL-25 expression contributes to lipid accumulation, whereas 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.
authors.affiliation: Department of Radiation Oncology, University of Maryland School of Medicine, Baltimore, MD 21201; Department of Medicine, University of Maryland School of Medicine, Baltimore, MD 21201; Department of Gastroenterology and Hepatology, First Affiliated Hospital of Nanchang University, Nanchang 330006, China;
authors.forename: An-Jiang
authors.initials: AJ
authors.lastname: Wang
authors.affiliation: Department of Radiation Oncology, University of Maryland School of Medicine, Baltimore, MD 21201; Department of Medicine, University of Maryland School of Medicine, Baltimore, MD 21201; Department of Biochemistry, Zhongshan Medical School, Sun Yat-sen University, Guangzhou 510080, China;
authors.forename: Zhonghan
authors.identifier: http://orcid.org/0000-0002-3009-4074
authors.initials: Z
authors.lastname: Yang
authors.affiliation: Department of Radiation Oncology, University of Maryland School of Medicine, Baltimore, MD 21201; Department of Medicine, University of Maryland School of Medicine, Baltimore, MD 21201;
authors.forename: Viktoriya
authors.initials: V
authors.lastname: Grinchuk
authors.affiliation: Diet, Genomics, and Immunology Laboratory, Agricultural Research Service, Beltsville Human Nutrition Research Center, U.S. Department of Agriculture, Beltsville, MD 20705;
authors.forename: Allen
authors.initials: A
authors.lastname: Smith
authors.affiliation: Department of Radiation Oncology, University of Maryland School of Medicine, Baltimore, MD 21201;
authors.forename: Bolin
authors.identifier: http://orcid.org/0000-0001-5823-5601
authors.initials: B
authors.lastname: Qin
authors.affiliation: Department of Gastroenterology and Hepatology, First Affiliated Hospital of Nanchang University, Nanchang 330006, China;
authors.forename: Nonghua
authors.initials: N
authors.lastname: Lu
authors.affiliation: Department of Pharmaceutical Sciences, University of Maryland School of Pharmacy, Baltimore, MD 21201; and.
authors.forename: Duan
authors.initials: D
authors.lastname: Wang
authors.affiliation: Department of Pharmaceutical Sciences, University of Maryland School of Pharmacy, Baltimore, MD 21201; and.
authors.forename: Hongbing
authors.initials: H
authors.lastname: Wang
authors.affiliation: Division of Parasitology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892.
authors.forename: Thirumalai R
authors.initials: TR
authors.lastname: Ramalingam
authors.affiliation: Division of Parasitology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892.
authors.forename: Thomas A
authors.initials: TA
authors.lastname: Wynn
authors.affiliation: Diet, Genomics, and Immunology Laboratory, Agricultural Research Service, Beltsville Human Nutrition Research Center, U.S. Department of Agriculture, Beltsville, MD 20705;
authors.forename: Joseph F
authors.initials: JF
authors.lastname: Urban
authors.affiliation: Department of Radiation Oncology, University of Maryland School of Medicine, Baltimore, MD 21201; Department of Medicine, University of Maryland School of Medicine, Baltimore, MD 21201;
authors.forename: Terez
authors.initials: T
authors.lastname: Shea-Donohue
authors.affiliation: Department of Radiation Oncology, University of Maryland School of Medicine, Baltimore, MD 21201; Department of Medicine, University of Maryland School of Medicine, Baltimore, MD 21201; aiping.zhao@nih.gov.
authors.forename: Aiping
authors.initials: A
authors.lastname: Zhao
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D004041:Dietary Fats / Q000009:adverse effects* / Q000494:pharmacology; D004195:Disease Models, Animal; D015536:Down-Regulation / Q000187:drug effects / Q000235:genetics / Q000276:immunology; D005234:Fatty Liver / Q000139:chemically induced / Q000235:genetics / Q000276:immunology* / Q000473:pathology / Q000517:prevention & control; D022781:Hepatocytes / Q000276:immunology / Q000473:pathology; D018793:Interleukin-13 / Q000235:genetics / Q000276:immunology*; D007378:Interleukins / Q000235:genetics / Q000276:immunology* / Q000494:pharmacology; D066292:Lipid Droplets / Q000276:immunology* / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D050800:STAT6 Transcription Factor / Q000235:genetics / Q000276:immunology*
chemical_list: D004041:Dietary Fats; D018793:Interleukin-13; D007378:Interleukins; C442281:Mydgf protein, mouse; D050800:STAT6 Transcription Factor; C494100:Stat6 protein, mouse