title: Dental infection of Porphyromonas gingivalis exacerbates high fat diet-induced steatohepatitis in mice.
abstract: BACKGROUND
  We investigated the effects of dental infection with Porphyromonas gingivalis (P.g.), an important periodontal pathogen, on NASH progression, by feeding mice a high fat diet (HFD)and examining P.g. infection in the liver of NASH patients.
  
  
  METHODS
  C57BL/6J mice were fed either chow-diet (CD) or HFD for 12 weeks, and then half of the mice in each group were infected with P.g. from the pulp chamber (HFD-P.g.(-), HFD-P.g.(+), CD-P.g.(-) and CD-P.g.(+)). Histological and immunohistochemical examinations, measurement of serum lipopolysaccharide (LPS) levels and ELISA for cytokines in the liver were performed. We then studied the effects of LPS from P.g. (P.g.-LPS) on palmitate-induced steatotic hepatocytes in vitro, and performed immunohistochemical detection of P.g. in liver biopsy specimens of NASH patients.
  
  
  RESULTS
  Serum levels of LPS are upregulated in P.g.(+) groups. Steatosis of the liver developed in HFD groups, and foci of Mac2-positive macrophages were prominent in HFD-P.g.(+). P.g. was detected in Kupffer cells and hepatocytes. Interestingly, areas of fibrosis with proliferation of hepatic stellate cells and collagen formation were only observed in HFD-P.g.(+). In steatotic hepatocytes, expression of TLR2, one of the P.g.-LPS receptors, was upregulated. P.g.-LPS further increased mRNA levels of palmitate-induced inflammasome and proinflammatory cytokines in steatotic hepatocytes. We demonstrated for the first time that P.g. existed in the liver of NASH patients with advanced fibrosis.
  
  
  CONCLUSIONS
  Dental infection of P.g. may play an important role in NASH progression through upregulation of the P.g.-LPS-TLR2 pathway and activation of inflammasomes. Therefore, preventing and/or eliminating P.g. infection by dental therapy may have a beneficial impact on management of NASH.
authors.affiliation: Department of Oral and Maxillofacial Pathobiology, Basic Life Sciences, Institute of Biomedical and Health Sciences, Hiroshima University, 1-2-3 Kasumi, Minami-ku, Hiroshima, 734-8553, Japan.
authors.forename: Hisako
authors.initials: H
authors.lastname: Furusho
authors.forename: Mutsumi
authors.initials: M
authors.lastname: Miyauchi
authors.forename: Hideyuki
authors.initials: H
authors.lastname: Hyogo
authors.forename: Toshihiro
authors.initials: T
authors.lastname: Inubushi
authors.forename: Min
authors.initials: M
authors.lastname: Ao
authors.forename: Kazuhisa
authors.initials: K
authors.lastname: Ouhara
authors.forename: Junzou
authors.initials: J
authors.lastname: Hisatune
authors.forename: Hidemi
authors.initials: H
authors.lastname: Kurihara
authors.forename: Motoyuki
authors.initials: M
authors.lastname: Sugai
authors.forename: C Nelson
authors.initials: CN
authors.lastname: Hayes
authors.forename: Takashi
authors.initials: T
authors.lastname: Nakahara
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Aikata
authors.forename: Shoichi
authors.initials: S
authors.lastname: Takahashi
authors.forename: Kazuaki
authors.initials: K
authors.lastname: Chayama
authors.forename: Takashi
authors.initials: T
authors.lastname: Takata
mesh_terms: D000328:Adult; D000368:Aged; D000818:Animals; D016866:Bacteroidaceae Infections / Q000150:complications* / Q000378:metabolism / Q000473:pathology; D001706:Biopsy; D002478:Cells, Cultured; D016207:Cytokines / Q000096:biosynthesis / Q000235:genetics; D059305:Diet, High-Fat / Q000009:adverse effects*; D004195:Disease Models, Animal; D018450:Disease Progression; D005234:Fatty Liver / Q000209:etiology* / Q000378:metabolism / Q000382:microbiology / Q000473:pathology; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects; D022781:Hepatocytes / Q000187:drug effects / Q000378:metabolism / Q000382:microbiology; D006801:Humans; D058847:Inflammasomes / Q000096:biosynthesis; D018836:Inflammation Mediators / Q000378:metabolism; D008099:Liver / Q000378:metabolism / Q000382:microbiology / Q000473:pathology; D008103:Liver Cirrhosis / Q000209:etiology / Q000378:metabolism / Q000382:microbiology / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008875:Middle Aged; D065626:Non-alcoholic Fatty Liver Disease; D010168:Palmitates / Q000494:pharmacology; D010484:Periapical Granuloma / Q000150:complications*; D016966:Porphyromonas gingivalis / Q000302:isolation & purification*; D012333:RNA, Messenger / Q000235:genetics; D051195:Toll-Like Receptor 2 / Q000096:biosynthesis; D015854:Up-Regulation
chemical_list: D016207:Cytokines; D058847:Inflammasomes; D018836:Inflammation Mediators; D010168:Palmitates; D012333:RNA, Messenger; C493486:Tlr2 protein, mouse; D051195:Toll-Like Receptor 2