title: Ligand-activated peroxisome proliferator-activated receptor-δ and -γ inhibit lipopolysaccharide-primed release of high mobility group box 1 through upregulation of SIRT1.
abstract: Peroxisome proliferator-activated receptors (PPARs) inhibit lipopolysaccharide (LPS)-primed release of high mobility group box 1 (HMGB1), a late proinflammatory mediator, but the underlying molecular mechanism is not completely understood. In this study, we demonstrated that the inhibition of HMGB1 release by PPAR-δ and -γ is associated with the deacetylase activity of SIRT1. Ligand-activated PPAR-δ and -γ inhibited LPS-primed release of HMGB1, concomitant with elevation in SIRT1 expression and promoter activity. These effects were significantly reduced in the presence of small interfering (si)RNAs against PPAR, indicating that PPAR-δ and -γ are involved in both HMGB1 release and SIRT1 expression. In addition, modulation of SIRT1 expression and activity by siRNA or chemicals correspondingly influenced the effects of PPARs on HMGB1 release, suggesting a mechanism in which SIRT1 modulates HMGB1 release. Furthermore, we showed for the first time that HMGB1 acetylated in response to LPS or p300/CBP-associated factor (PCAF) is an effective substrate for SIRT1, and that deacetylation of HMGB1 is responsible for blockade of HMGB1 release in macrophages. Finally, acetylation of HMGB1 was elevated in mouse embryonic fibroblasts from SIRT1-knockout mice, whereas this increase was completely reversed by ectopic expression of SIRT1. These results indicate that PPAR-mediated upregulation of SIRT1 modulates the status of HMGB1 acetylation, which, in turn, has a critical role in the cellular response to inflammation through deacetylation-mediated regulation of HMGB1 release.
authors.affiliation: Department of Animal Biotechnology, Konkuk University, Seoul, Republic of Korea.
authors.forename: J S
authors.initials: JS
authors.lastname: Hwang
authors.affiliation: Department of Animal Biotechnology, Konkuk University, Seoul, Republic of Korea.
authors.forename: W J
authors.initials: WJ
authors.lastname: Lee
authors.affiliation: Department of Animal Biotechnology, Konkuk University, Seoul, Republic of Korea.
authors.forename: E S
authors.initials: ES
authors.lastname: Kang
authors.affiliation: Department of Animal Biotechnology, Konkuk University, Seoul, Republic of Korea.
authors.forename: S A
authors.initials: SA
authors.lastname: Ham
authors.affiliation: Department of Animal Biotechnology, Konkuk University, Seoul, Republic of Korea.
authors.forename: T
authors.initials: T
authors.lastname: Yoo
authors.affiliation: Department of Nursing, Semyung University, Jecheon, Republic of Korea.
authors.forename: K S
authors.initials: KS
authors.lastname: Paek
authors.affiliation: Department of Applied Bioscience, College of Life Science, CHA University, Seongnam, Korea.
authors.forename: D S
authors.initials: DS
authors.lastname: Lim
authors.affiliation: Department of Animal Biotechnology, Konkuk University, Seoul, Republic of Korea.
authors.forename: J T
authors.initials: JT
authors.lastname: Do
authors.affiliation: Department of Animal Biotechnology, Konkuk University, Seoul, Republic of Korea.
authors.forename: H G
authors.initials: HG
authors.lastname: Seo
mesh_terms: D000818:Animals; D002460:Cell Line; D015536:Down-Regulation; D024243:HMGB1 Protein / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D008070:Lipopolysaccharides / Q000378:metabolism*; D008264:Macrophages / Q000201:enzymology / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D047494:PPAR delta / Q000235:genetics / Q000378:metabolism*; D047495:PPAR gamma / Q000235:genetics / Q000378:metabolism*; D056564:Sirtuin 1 / Q000235:genetics* / Q000378:metabolism; D015854:Up-Regulation; D050880:p300-CBP Transcription Factors / Q000235:genetics / Q000378:metabolism; D000099224:p300-CBP-Associated Factor
chemical_list: D024243:HMGB1 Protein; D008070:Lipopolysaccharides; D047494:PPAR delta; D047495:PPAR gamma; D056564:Sirtuin 1; D050880:p300-CBP Transcription Factors; D000099224:p300-CBP-Associated Factor; C470545:Sirt1 protein, mouse