TY - JOUR
T1 - Outer membrane vesicles of Porphyromonas gingivalis attenuate insulin sensitivity by delivering gingipains to the liver
AU - Seyama, Mariko
AU - Yoshida, Kaya
AU - Yoshida, Kayo
AU - Fujiwara, Natsumi
AU - Ono, Kisho
AU - Eguchi, Takanori
AU - Kawai, Hotaka
AU - Guo, Jiajie
AU - Weng, Yao
AU - Haoze, Yuan
AU - Uchibe, Kenta
AU - Ikegame, Mika
AU - Sasaki, Akira
AU - Nagatsuka, Hitoshi
AU - Okamoto, Kuniaki
AU - Okamura, Hirohiko
AU - Ozaki, Kazumi
N1 - Funding Information:
We thank Professor Koji Nakayama (Nagasaki University) and Dr. Mikio Shoji (Nagasaki University) for the Pg gingipain-mutant strains, Dr. Tomoko Kadowaki (Nagasaki University) for gingipain antibodies, the Support Center for Advanced Medical Sciences (Institute of Health Biosciences, University of Tokushima Graduate School) for LC-MS/MS analyses and technical support. We also thank Mr. Haruo Urata and Mses. Masumi Furutani and Moemi Tsukano (Central research Laboratory, Okayama University) for electron microscopy observation. This study was supported by a grant-in-Aid for Scientific Research from the Ministry of Education, Science, Sports, and Culture of Japan (16K11506, Kaya Y; 17K11642, TE), the SHISEIKAI Scientific Award, Shiseikai Association (Kaya Y), Kobayashi Magobe Memorial Medical Foundation (Kaya Y) and Suzuken Memorial Foundation (HO). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. The authors declare no competing financial interests. Kaya Yoshida, H. Okamura, and K. Ozaki conceived and supervised the project. M. Seyama, Kaya Yoshida, Kayo Yoshida, N. Fujiwara, K. Uchibe, and M Ikegame performed the majority of the experiments. K. Ono, T. Eguchi, A. Sasaki, and K. Okamoto isolated and analyzed the OMVs. H. Kawai and H. Nagatsuka contributed to the pathological diagnosis, PAS staining, and immunohistochemistry. Y. Weng, H. Yuan, and J. Guo designed the figures. K. Yoshida and H. Okamura wrote the manuscript with input from all authors. T. Eguchi edited the manuscript.
Funding Information:
This study was supported by a grant-in-Aid for Scientific Research from the Ministry of Education, Science, Sports, and Culture of Japan ( 16K11506 , Kaya Y; 17K11642 , TE), the SHISEIKAI Scientific Award , Shiseikai Association (Kaya Y), Kobayashi Magobe Memorial Medical Foundation (Kaya Y) and Suzuken Memorial Foundation (HO). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
Publisher Copyright:
© 2020 Elsevier B.V.
PY - 2020/6/1
Y1 - 2020/6/1
N2 - Outer membrane vesicles (OMVs) are nanosized particles derived from the outer membrane of gram-negative bacteria. Oral bacterium Porphyromonas gingivalis (Pg) is known to be a major pathogen of periodontitis that contributes to the progression of periodontal disease by releasing OMVs. The effect of Pg OMVs on systemic diseases is still unknown. To verify whether Pg OMVs affect the progress of diabetes mellitus, we analyzed the cargo proteins of vesicles and evaluated their effect on hepatic glucose metabolism. Here, we show that Pg OMVs were equipped with Pg-derived proteases gingipains and translocated to the liver in mice. In these mice, the hepatic glycogen synthesis in response to insulin was decreased, and thus high blood glucose levels were maintained. Pg OMVs also attenuated the insulin-induced Akt/glycogen synthase kinase-3 β (GSK-3β) signaling in a gingipain-dependent fashion in hepatic HepG2 cells. These results suggest that the delivery of gingipains mediated by Pg OMV elicits changes in glucose metabolisms in the liver and contributes to the progression of diabetes mellitus.
AB - Outer membrane vesicles (OMVs) are nanosized particles derived from the outer membrane of gram-negative bacteria. Oral bacterium Porphyromonas gingivalis (Pg) is known to be a major pathogen of periodontitis that contributes to the progression of periodontal disease by releasing OMVs. The effect of Pg OMVs on systemic diseases is still unknown. To verify whether Pg OMVs affect the progress of diabetes mellitus, we analyzed the cargo proteins of vesicles and evaluated their effect on hepatic glucose metabolism. Here, we show that Pg OMVs were equipped with Pg-derived proteases gingipains and translocated to the liver in mice. In these mice, the hepatic glycogen synthesis in response to insulin was decreased, and thus high blood glucose levels were maintained. Pg OMVs also attenuated the insulin-induced Akt/glycogen synthase kinase-3 β (GSK-3β) signaling in a gingipain-dependent fashion in hepatic HepG2 cells. These results suggest that the delivery of gingipains mediated by Pg OMV elicits changes in glucose metabolisms in the liver and contributes to the progression of diabetes mellitus.
KW - Diabetes mellitus
KW - Insulin resistance
KW - Outer membrane vesicles
KW - Periodontal disease
KW - Porphyromonas gingivalis
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U2 - 10.1016/j.bbadis.2020.165731
DO - 10.1016/j.bbadis.2020.165731
M3 - Article
C2 - 32088316
AN - SCOPUS:85080033827
VL - 1866
JO - Biochimica et Biophysica Acta - Molecular Basis of Disease
JF - Biochimica et Biophysica Acta - Molecular Basis of Disease
SN - 0925-4439
IS - 6
M1 - 165731
ER -
