Porphyromonas gingivalis attenuates the insulin-induced phosphorylation and translocation of forkhead box protein O1 in human hepatocytes.

OBJECTIVE: Porphyromonas gingivalis (P. gingivalis) is a pathogen involved in periodontal disease. Recently, periodontal disease has been demonstrated to increase the risk of developing diabetes mellitus, although the molecular mechanism is not fully understood. Forkhead box protein O1 (FoxO1) is a transcriptional factor that regulates gluconeogenesis in the liver. Gluconeogenesis is a key process in the induction of diabetes mellitus; however, little is known regarding the relationship between periodontal disease and gluconeogenesis. In this study, to investigate whether periodontal disease influences hepatic gluconeogenesis, we examined the effects of P. gingivalis on the phosphorylation and translocation of FoxO1 in insulin-induced human hepatocytes. DESIGN: The human hepatocyte HepG2 was treated with insulin and Akt and FoxO1 phosphorylation was detected by western blot analysis. The localization of phosphorylated FoxO1 was detected by immunocytochemistry and western blot analysis. HepG2 cells were treated with SNAP26b-tagged P. gingivalis (SNAP-P.g.) before insulin stimulation, and then the changes in Akt and FoxO1 were determined by western blot analysis and immunocytochemistry. RESULTS: Insulin (100nM) induced FoxO1 phosphorylation 60min after treatment in HepG2 cells. Phosphorylated FoxO1 translocated to the cytoplasm. SNAP-P.g. internalized into HepG2 cells and decreased Akt and FoxO1 phosphorylation induced by insulin. The effect of insulin on FoxO1 translocation was also attenuated by SNAP-P.g. CONCLUSIONS: Our study shows that P. gingivalis decreases the phosphorylation and translocation of FoxO induced by insulin in HepG2 cells. Our results suggest that periodontal disease may increase hepatic gluconeogenesis by reducing the effects of insulin on FoxO1.

Oral Porphyromonas gingivalis translocates to the liver and regulates hepatic glycogen synthesis through the Akt/GSK-3ß signaling pathway.

Periodontal diseases are common chronic inflammatory disorders that result in the destruction of tissues around teeth. Many clinical studies suggest that periodontal diseases are risk factors for insulin resistance and diabetic mellitus development. However, the molecular mechanisms by which periodontal diseases regulate the progress of diabetes mellitus remain unknown. In this study, we investigated whether Porphyromonas gingivalis (P.g.), a major pathogen of periodontal diseases, present in the oral cavity, moves to the liver and affects hepatic glycogen synthesis. SNAP26b-tagged P.g. (SNAP-P.g.) was introduced into the oral cavity to induce periodontal disease in 4-week old female Balb/c mice. SNAP-P.g. was detected in the liver extracted from SNAP-P.g.-treated mice using nested PCR analysis. High blood glucose levels tended to promote SNAP-P.g. translocation from the oral cavity to the liver in mice. Periodic acid-Schiff staining suggested that hepatic glycogen synthesis decreased in SNAP-P.g.-treated mice. SNAP-P.g. was also internalized into the human hepatoma cell line HepG2, and this attenuated the phosphorylation of insulin receptor substrate (IRS)-1, Akt and glycogen synthase kinase-3ß induced by insulin. Insulin-induced glycogen synthesis was suppressed by SNAP-P.g. in HepG2 cells. Our results suggest that P.g. translocation from the oral cavity to the liver may contribute to the progress of diabetes mellitus by influencing hepatic glycogenesis.