Effect of Porphyromonas gingivalis infection on post-transcriptional regulation of the low-density lipoprotein receptor in mice

Lipids in Health and Disease

Kazuhisa Yamazaki¹  Takako Nakajima³  Tomoyuki Honda¹  Hisanori Domon²  Yukari Aoki-Nonaka¹  Sayuri Miyauchi¹  Koichi Tabeta²  Haruna Miyazawa¹ 

[1] Laboratory of Periodontology and Immunology, Division of Oral Science for Health Promotion, Niigata University Graduate School of Medical and Dental Sciences, 5274 Gakkocho 2-ban-cho, Chu-o-ku, Niigata, 951-8514, Japan;Center for Transdisciplinary Research, Niigata University, 5274 Gakkocho 2-ban-cho, Chu-o-ku, Niigata, 951-8514, Japan;General Dentistry and Clinical Education Unit, Niigata University Medical and Dental Hospital, 5274 Gakkocho 2-ban-cho, Chu-o-ku, Niigata, 951-8514, Japan

关键词: Chronic inflammation;    Periodontitis;    LDL cholesterol;    PCSK9;   

Others  :  1160197
DOI  :  10.1186/1476-511X-11-121

 received in 2012-05-24, accepted in 2012-09-14,  发布年份 2012

【 摘 要 】

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.

【 授权许可】

   
2012 Miyazawa et al.; licensee BioMed Central Ltd.

【 图 表 】

Figure 1.

Figure 2.

Figure 3.

Figure 4.

Figure 5.

【 参考文献 】

• [1]Katz J, Flugelman MY, Goldberg A, Heft M: Association between periodontal pockets and elevated cholesterol and low density lipoprotein cholesterol levels. J Periodontol 2002, 73:494-500.
• [2]Losche W, Karapetow F, Pohl A, Pohl C, Kocher T: Plasma lipid and blood glucose levels in patients with destructive periodontal disease. J Clin Periodontol 2000, 27:537-541.
• [3]D'Aiuto F, Nibali L, Parkar M, Suvan J, Tonetti MS: Short-term effects of intensive periodontal therapy on serum inflammatory markers and cholesterol. J Dent Res 2005, 84:269-273.
• [4]Yokoyama C, Wang X, Briggs MR, Admon A, Wu J, Hua X, Goldstein JL, Brown MS: SREBP-1, a basic-helix-loop-helix-leucine zipper protein that controls transcription of the low density lipoprotein receptor gene. Cell 1993, 75:187-197.
• [5]Zelcer N, Hong C, Boyadjian R, Tontonoz P: LXR regulates cholesterol uptake through Idol-dependent ubiquitination of the LDL receptor. Science 2009, 325:100-104.
• [6]Lambert G, Charlton F, Rye KA, Piper DE: Molecular basis of PCSK9 function. Atherosclerosis 2009, 203:1-7.
• [7]Seidah NG, Benjannet S, Wickham L, Marcinkiewicz J, Jasmin SB, Stifani S, Basak A, Prat A, Chretien M: The secretory proprotein convertase neural apoptosis-regulated convertase 1 (NARC-1): liver regeneration and neuronal differentiation. Proc Natl Acad Sci US A 2003, 100:928-933.
• [8]Zhang DW, Lagace TA, Garuti R, Zhao Z, McDonald M, Horton JD, Cohen JC, Hobbs HH: Binding of proprotein convertase subtilisin/kexin type 9 to epidermal growth factor-like repeat A of low density lipoprotein receptor decreases receptor recycling and increases degradation. J Biol Chem 2007, 282:18602-18612.
• [9]Miyazawa H, Honda T, Miyauchi S, Domon H, Okui T, Nakajima T, Tabeta K, Yamazaki K: Increased serum PCSK9 concentrations are associated with periodontal infection but do not correlate with LDL cholesterol concentration. Clin Chim Acta 2012, 413:154-159.
• [10]Khovidhunkit W, Kim MS, Memon RA, Shigenaga JK, Moser AH, Feingold KR, Grunfeld C: Effects of infection and inflammation on lipid and lipoprotein metabolism: mechanisms and consequences to the host. J Lipid Res 2004, 45:1169-1196.
• [11]Feingold KR, Moser AH, Shigenaga JK, Patzek SM, Grunfeld C: Inflammation stimulates the expression of PCSK9. Biochem BiophysRes Commun 2008, 374:341-344.
• [12]Cohen J, Pertsemlidis A, Kotowski IK, Graham R, Garcia CK, Hobbs HH: Low LDL cholesterol in individuals of African descent resulting from frequent nonsense mutations in PCSK9. Nat Genet 2005, 37:161-165.
• [13]Rashid S, Curtis DE, Garuti R, Anderson NN, Bashmakov Y, Ho YK, Hammer RE, Moon YA, Horton JD: Decreased plasma cholesterol and hypersensitivity to statins in mice lacking Pcsk9. Proc Natl Acad Sci U S A 2005, 102:5374-5379.
• [14]Abifadel M, Varret M, Rabes JP, Allard D, Ouguerram K, Devillers M, Cruaud C, Benjannet S, Wickham L, Erlich D, et al.: Mutations in PCSK9 cause autosomal dominant hypercholesterolemia. Nat Genet 2003, 34:154-156.
• [15]Lambert G, Krempf M, Costet P: PCSK9: a promising therapeutic target for dyslipidemias? Trends Endocrinol Metab 2006, 17:79-81.
• [16]Maekawa T, Takahashi N, Tabeta K, Aoki Y, Miyashita H, Miyauchi S, Miyazawa H, Nakajima T, Yamazaki K: Chronic Oral Infection with Porphyromonas gingivalis accelerates atheroma formation by shifting the lipid profile. PLoS ONE 2011, 6:e20240.
• [17]Dubuc G, Chamberland A, Wassef H, Davignon J, Seidah NG, Bernier L, Prat A: Statins upregulate PCSK9, the gene encoding the proprotein convertase neural apoptosis-regulated convertase-1 implicated in familial hypercholesterolemia. Arterioscler Thromb Vasc Biol 2004, 24:1454-1459.
• [18]Jeong HJ, Lee HS, Kim KS, Kim YK, Yoon D, Park SW: Sterol-dependent regulation of proprotein convertase subtilisin/kexin type 9 expression by sterol-regulatory element binding protein-2. J Lipid Res 2008, 49:399-409.
• [19]Li H, Dong B, Park SW, Lee HS, Chen W, Liu J: Hepatocyte nuclear factor 1alpha plays a critical role in PCSK9 gene transcription and regulation by the natural hypocholesterolemic compound berberine. J Biol Chem 2009, 284:28885-28895.
• [20]Du F, Hui Y, Zhang M, Linton MF, Fazio S, Fan D: Novel domain interaction regulates secretion of proprotein convertase subtilisin/kexin type 9 (PCSK9) protein. J Biol Chem 2011, 286:43054-43061.
• [21]Sorrentino V, Zelcer N: Post-transcriptional regulation of lipoprotein receptors by the E3-ubiquitin ligase inducible degrader of the low-density lipoprotein receptor. Curr Opin Lipidol 2012, 23(3):213-219.