title: Effect of Porphyromonas gingivalis infection on post-transcriptional regulation of the low-density lipoprotein receptor in mice.
abstract: BACKGROUND
  Periodontal disease is suggested to increase the risk of atherothrombotic disease by inducing dyslipidemia. Recently, we demonstrated that proprotein convertase subtilisin/kexin type 9 (PCSK9), which is known to play a critical role in the regulation of circulating low-density lipoprotein (LDL) cholesterol levels, is elevated in periodontitis patients. However, the underlying mechanisms of elevation of PCSK9 in periodontitis patients are largely unknown. Here, we explored whether Porphyromonas gingivalis, a representative periodontopathic bacterium, -induced inflammatory response regulates serum PCSK9 and cholesterol levels using animal models.
  
  
  METHODS
  We infected C57BL/6 mice intraperitoneally with Porphyromonas gingivalis, a representative strain of periodontopathic bacteria, and evaluated serum PCSK9 levels and the serum lipid profile. PCSK9 and LDL receptor (LDLR) gene and protein expression, as well as liver X receptors (Lxrs), inducible degrader of the LDLR (Idol), and sterol regulatory element binding transcription factor (Srebf)2 gene expression, were examined in the liver.
  
  
  RESULTS
  P. gingivalis infection induced a significant elevation of serum PCSK9 levels and a concomitant elevation of total and LDL cholesterol compared with sham-infected mice. The LDL cholesterol levels were significantly correlated with PCSK9 levels. Expression of the Pcsk9, Ldlr, and Srebf2 genes was upregulated in the livers of the P. gingivalis-infected mice compared with the sham-infected mice. Although Pcsk9 gene expression is known to be positively regulated by sterol regulatory element binding protein (SREBP)2 (human homologue of Srebf2), whereas Srebf2 is negatively regulated by cholesterol, the elevated expression of Srebf2 found in the infected mice is thought to be mediated by P. gingivalis infection.
  
  
  CONCLUSIONS
  P. gingivalis infection upregulates PCSK9 production via upregulation of Srebf2, independent of cholesterol levels. Further studies are required to elucidate how infection regulates Srebf2 expression and subsequently influences lipid metabolism.
authors.affiliation: Center for Transdisciplinary Research, Niigata University, 5274 Gakkocho 2-ban-cho, Niigata, 951-8514, Japan.
authors.forename: Haruna
authors.initials: H
authors.lastname: Miyazawa
authors.forename: Koichi
authors.initials: K
authors.lastname: Tabeta
authors.forename: Sayuri
authors.initials: S
authors.lastname: Miyauchi
authors.forename: Yukari
authors.initials: Y
authors.lastname: Aoki-Nonaka
authors.forename: Hisanori
authors.initials: H
authors.lastname: Domon
authors.forename: Tomoyuki
authors.initials: T
authors.lastname: Honda
authors.forename: Takako
authors.initials: T
authors.lastname: Nakajima
authors.forename: Kazuhisa
authors.initials: K
authors.lastname: Yamazaki
mesh_terms: D000818:Animals; D016866:Bacteroidaceae Infections / Q000097:blood / Q000235:genetics* / Q000378:metabolism*; D002784:Cholesterol / Q000097:blood; D008078:Cholesterol, LDL / Q000097:blood; D004195:Disease Models, Animal; D015870:Gene Expression; D006801:Humans; D008055:Lipids / Q000097:blood; D008099:Liver / Q000378:metabolism; D000071518:Liver X Receptors; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D057093:Orphan Nuclear Receptors / Q000235:genetics / Q000378:metabolism; D016966:Porphyromonas gingivalis / Q000472:pathogenicity; D000071449:Proprotein Convertase 9; D043484:Proprotein Convertases / Q000097:blood / Q000235:genetics; D012323:RNA Processing, Post-Transcriptional; D011973:Receptors, LDL / Q000235:genetics* / Q000378:metabolism*; D012697:Serine Endopeptidases / Q000097:blood / Q000235:genetics; D051782:Sterol Regulatory Element Binding Protein 2 / Q000235:genetics / Q000378:metabolism; D044767:Ubiquitin-Protein Ligases / Q000235:genetics / Q000378:metabolism; D015854:Up-Regulation
chemical_list: D008078:Cholesterol, LDL; D008055:Lipids; D000071518:Liver X Receptors; D057093:Orphan Nuclear Receptors; D011973:Receptors, LDL; C497391:Srebf2 protein, mouse; D051782:Sterol Regulatory Element Binding Protein 2; D002784:Cholesterol; C542022:Mylip protein, mouse; D044767:Ubiquitin-Protein Ligases; C472126:Pcsk9 protein, mouse; D000071449:Proprotein Convertase 9; D043484:Proprotein Convertases; D012697:Serine Endopeptidases