title: Glucocorticoid Induces Hepatic Steatosis by Inhibiting Activating Transcription Factor 3 (ATF3)/S100A9 Protein Signaling in Granulocytic Myeloid-derived Suppressor Cells.
abstract: Glucocorticoids (GCs) used as inflammation suppressors have harmful side effects, including induction of hepatic steatosis. The underlying mechanisms of GC-promoted dysregulation of lipid metabolism, however, are not fully understood. GCs could facilitate the accumulation of myeloid-derived suppressor cells (MDSC) in the liver of animals, and the potential role of MDSCs in GC-induced hepatic steatosis was therefore investigated in this study. We demonstrated that granulocytic (G)-MDSC accumulation mediated the effects of GCs on the fatty liver, in which activating transcription factor 3 (ATF3)/S100A9 signaling plays an important role. ATF3-deficient mice developed hepatic steatosis and displayed expansion of G-MDSCs in the liver and multiple immune organs, which shared high similarity with the phenotype observed in GC-treated wild-type littermates. Adoptive transfer of GC-induced or ATF3-deficient G-MDSCs promoted lipid accumulation in the liver, whereas depletion of G-MDSCs alleviated these effects. Mechanistic studies showed that in MDSCs, ATF3 was transrepressed by the GC receptor GR through direct binding to the negative GR-response element. S100A9 is the major transcriptional target of ATF3 in G-MDSCs. Silencing S100A9 clearly alleviated G-MDSCs expansion and hepatic steatosis caused by ATF3 deficiency or GC treatment. Our study uncovers an important role of G-MDSCs in GC-induced hepatic steatosis, in which ATF3 may have potential therapeutic implications.
authors: From the Program in Immunology, Affiliated Guangzhou Women and Children's Medical Center, Zhongshan School of Medicine, 9th Jin Sui Road, Guangzhou 510623, and.|Institute of Human Virology, Sun Yat-Sen University, 74 Zhongshan 2nd Road, Guangzhou 510080.|the Department of Hematology Oncology, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, 9th Jin Sui Road, Guangzhou 510623, China.
authors: Yu-Feng
authors: YF
authors: Liu
authors: Institute of Human Virology, Sun Yat-Sen University, 74 Zhongshan 2nd Road, Guangzhou 510080.
authors: Jian-Yang
authors: JY
authors: Wei
authors: Institute of Human Virology, Sun Yat-Sen University, 74 Zhongshan 2nd Road, Guangzhou 510080.
authors: Mao-Hua
authors: MH
authors: Shi
authors: From the Program in Immunology, Affiliated Guangzhou Women and Children's Medical Center, Zhongshan School of Medicine, 9th Jin Sui Road, Guangzhou 510623, and.|the Department of Hematology Oncology, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, 9th Jin Sui Road, Guangzhou 510623, China.
authors: Hua
authors: H
authors: Jiang
authors: From the Program in Immunology, Affiliated Guangzhou Women and Children's Medical Center, Zhongshan School of Medicine, 9th Jin Sui Road, Guangzhou 510623, and zhouj72@mail.sysu.edu.cn.|Institute of Human Virology, Sun Yat-Sen University, 74 Zhongshan 2nd Road, Guangzhou 510080.|the Key Laboratory of Tropical Disease Control (Sun Yat-Sen University), Chinese Ministry of Education, 74 Zhongshan 2nd Road, Guangzhou 510080, and.
authors: Jie
authors: J
authors: Zhou
mesh_terms: D051700:Activating Transcription Factor 3 / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D040502:Calgranulin B / Q000235:genetics / Q000378:metabolism*; D005234:Fatty Liver / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D020868:Gene Silencing; D005938:Glucocorticoids / Q000378:metabolism*; D006098:Granulocytes / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D015398:Signal Transduction
chemical_list: D051700:Activating Transcription Factor 3; C103002:Atf3 protein, mouse; D040502:Calgranulin B; D005938:Glucocorticoids; C576329:S100A9 protein, mouse
keywords: S100 proteins; cAMP response element-binding protein; glucocorticoid; immunosuppression; liver metabolism