Upregulation of MKP-7 in response to rosiglitazone treatment ameliorates lipopolysaccharide-induced destabilization of SIRT1 by inactivating JNK

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• 作者：Jung Seok Hwang^a ; Sun Ah Ham^a ; Taesik Yoo^a ; Won Jin Lee^a ; Kyung Shin Paek^b ; Jae-Hwan Kim^c ; Chi-Ho Lee^a ; Han Geuk Seo^a ; ^{hgseo@konkuk.ac.kr}
• 关键词：SIRT1 ; silent mating type information regulation 2 homolog 1 ; PPARγ ; peroxisome proliferator-activated receptor γ ; LPS ; lipopolysaccharide ; MKP-7 ; mitogen-activated protein kinase phosphatase-7 ; PGC-1α ; peroxisome proliferator-activated receptor gamma coactivator-1α ; NF-κB ; nuclear factor kappa B ; AP-1 ; activator protein-1 ; HMGB1 ; high mobility group box 1 ; JNK1 ; c-Jun N-terminal kinase 1 ; MDM2 ; mouse double minute 2 homolog ; USP-22 ; ubiquitin-specific protease-22 ; PPRE ; PPAR-response element ; S
• 刊名：Pharmacological Research
• 出版年：2016
• 出版时间：December 2016
• 年：2016
• 卷：114
• 期：Complete
• 页码：47-55
• 全文大小：2067 K
• 卷排序：114

文摘

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.