Dental infection of Porphyromonas gingivalis exacerbates high fat diet-induced steatohepatitis in mice
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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.
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.
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.
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.
KeywordsNASH Dental infection P. gingivalis Fibrosis TLRs
Non-alcoholic fatty liver disease
Free fatty acid
High fat diet
Hematoxylin and Eosin
α-smooth muscle actin
Nod-like receptor 3
The authors thank Ryo Matsuda, Mao Muroi and Shinnichi Sakamoto for their support of this project. We are also grateful to Professor Kazuyuki Ishihara (Tokyo Dental College) for providing P.g.-specific polyclonal antibodies and Prof. Hidetoshi Tahara (Hiroshima University) for providing Hc3716-hTERT cells.
Conflict of interest
The authors declare that they have no conflict of interest.
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