title: Upregulation of MKP-7 in response to rosiglitazone treatment ameliorates lipopolysaccharide-induced destabilization of SIRT1 by inactivating JNK.
abstract: Silent mating type information regulation 2 homolog 1 (SIRT1), a NAD-dependent deacetylase, mediates cellular processes involved in gene silencing and aging. The regulation of lifespan by SIRT1 has been extensively investigated, but less is known about the mechanisms associated with its cellular turnover during inflammatory responses. In this study, we found that peroxisome proliferator-activated receptor (PPAR) γ is associated with SIRT1 stability in murine macrophage RAW 264.7 cells exposed to lipopolysaccharide (LPS). Activation of PPARγ by rosiglitazone, a specific ligand of PPARγ, rescues LPS-induced destabilization of SIRT1, with a concomitant decrease in phosphorylation of residue Ser-46, which is targeted by JNK-1 to promote proteasome-mediated degradation of SIRT1. The rosiglitazone-mediated increase in SIRT1 stability is accompanied by upregulation of mitogen-activated protein kinase phosphatase (MKP)-7, a JNK-specific phosphatase. These effects are significantly influenced by ablation or ectopic expression of PPARγ, indicating that PPARγ is directly involved in the regulation of SIRT1 stability. Furthermore, gain of MKP-7 function mimicked the effect of rosiglitazone on LPS-induced destabilization and ubiquitination of SIRT1. These results indicate that PPARγ-dependent upregulation of MKP-7 improves the stability of SIRT1 by inactivating JNK during inflammatory responses of LPS-activated macrophages.
authors: College of Animal Bioscience & Technology, Konkuk University, 120 Neungdong-ro, Gwangjin-gu, Seoul 05029, Republic of Korea.
authors: Jung Seok
authors: JS
authors: Hwang
authors: College of Animal Bioscience & Technology, Konkuk University, 120 Neungdong-ro, Gwangjin-gu, Seoul 05029, Republic of Korea.
authors: Sun Ah
authors: SA
authors: Ham
authors: College of Animal Bioscience & Technology, Konkuk University, 120 Neungdong-ro, Gwangjin-gu, Seoul 05029, Republic of Korea.
authors: Taesik
authors: T
authors: Yoo
authors: College of Animal Bioscience & Technology, Konkuk University, 120 Neungdong-ro, Gwangjin-gu, Seoul 05029, Republic of Korea.
authors: Won Jin
authors: WJ
authors: Lee
authors: Department of Nursing, Semyung University, Semyung-ro, Jechon, Chungbuk 390-711, Republic of Korea.
authors: Kyung Shin
authors: KS
authors: Paek
authors: Department of Biomedical Science, CHA University, Seongnam, Gyeonggi-Do 463-400, Republic of Korea.
authors: Jae-Hwan
authors: JH
authors: Kim
authors: College of Animal Bioscience & Technology, Konkuk University, 120 Neungdong-ro, Gwangjin-gu, Seoul 05029, Republic of Korea.
authors: Chi-Ho
authors: CH
authors: Lee
authors: College of Animal Bioscience & Technology, Konkuk University, 120 Neungdong-ro, Gwangjin-gu, Seoul 05029, Republic of Korea. Electronic address: hgseo@konkuk.ac.kr.
authors: Han Geuk
authors: HG
authors: Seo
mesh_terms: D000818:Animals; D016466:CHO Cells; D003412:Cricetulus; D054637:Dual-Specificity Phosphatases / Q000276:immunology*; D006801:Humans; D007004:Hypoglycemic Agents / Q000494:pharmacology*; D008070:Lipopolysaccharides / Q000276:immunology*; D008264:Macrophages / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism; D051379:Mice; D048055:Mitogen-Activated Protein Kinase 8 / Q000037:antagonists & inhibitors* / Q000276:immunology; D054639:Mitogen-Activated Protein Kinase Phosphatases / Q000276:immunology*; D047495:PPAR gamma / Q000276:immunology; D059748:Proteolysis / Q000187:drug effects; D000067996:RAW 264.7 Cells; D000077154:Rosiglitazone; D056564:Sirtuin 1 / Q000276:immunology* / Q000378:metabolism; D045162:Thiazolidinediones / Q000494:pharmacology*; D015854:Up-Regulation / Q000187:drug effects
chemical_list: D007004:Hypoglycemic Agents; D008070:Lipopolysaccharides; D047495:PPAR gamma; D045162:Thiazolidinediones; D000077154:Rosiglitazone; D048055:Mitogen-Activated Protein Kinase 8; D054639:Mitogen-Activated Protein Kinase Phosphatases; D054637:Dual-Specificity Phosphatases; C438002:Dusp16 protein, mouse; C470545:Sirt1 protein, mouse; D056564:Sirtuin 1
keywords: Lipopolysaccharide; Mitogen-activated protein kinase phosphatase (MKP)-7; Peroxisome proliferator-activated receptor γ; Rosiglitazone; SIRT1