Abstract
Recent studies have suggested that the periodontal disease, chronic sub-clinical inflammation,
is associated with atherosclerosis, although “cause or effect” relationship is still
unclear. The aim of this study was to assess the association between the degree of
periodontal infection and lipid profiles in diabetic subjects. Additionally, the association
of such sub-clinical inflammation with HMG-CoA reductase gene expression was evaluated.
One hundred and thirty-one non-obese relatively well-controlled Japanese type 2 diabetic
patients were enrolled for the study. Although no significant association was observed
between serum triglycerides, HLD-cholesterol and antibody titer to Porphyromonas gingivalis (Pg), the most predominant periodontal pathogen in adults, LDL-cholesterol was significantly
associated with antibody titer to Pg. Concomitantly, the same works out to be true
for total cholesterol. To understand the possible mechanisms underlying this association,
we evaluated 3-hydroxy-3-methylglutaryl-CoA (HMG-CoA) reductase gene expression in
cultured HepG2 cells stimulated by either bacterial lipopolysaccharide (LPS) or inflammatory
cytokines. Although Pg and E. coli LPS had no effect on HMG-CoA reductase gene expression, both tumor necrosis factor-α
and interleukin-6 (IL-6), especially IL-6 at low concentration, markedly up-regulated
HMG-CoA reductase gene expression. It can be concluded that Pg infection is associated
with increased LDL-cholesterol in diabetic subjects, which may be accompanied by increased
cholesterol synthesis by inflammatory cytokines.
Key words
Infection - diabetes - atherosclerosis - dyslipidemia - HMG-CoA reductase
References
1
Bierman EL.
George Lyman Duff Memorial Lecture. Atherogenesis in diabetes.
Arterioscler Thromb Vasc Biol.
1992;
12
647-656
2
UK Prospective Diabetes Study (UKPDS) Group .
Intensive blood-glucose control with sulphonylureas or insulin compared with conventional
treatment and risk of complications in patients with type 2 diabetes (UKPDS 33).
Lancet.
1998;
352
837-853
3
Ridker PM, Cushman M, Stampfer MJ. >et al .
Inflammation, aspirin, and the risk of cardiovascular disease in apparently healthy
men.
N Engl J Med.
1997;
336
973-979
4
Nelson RG, Shlossman M, Budding LM. >et al .
Periodontal disease and NIDDM in Pima Indians.
Diabetes Care.
1990;
13
836-840
5
Taniguchi A, Nishimura F, Murayama Y. >et al .
Porphyromonas gingivalis infection is associated with carotid atherosclerosis in non-obese
Japanese type 2 diabetic patients.
Metabolism.
2003;
52
142-145
6
DeStefano F, Anda RF, Kahn HS. >et al .
Dental disease and risk of coronary heart disease and mortality.
BMJ.
1993;
306
688-691
7
Saremi A, Nelson RG, Tulloch-Reid M. >et al .
Periodontal disease and mortality in type 2 diabetes.
Diabetes Care.
2005;
28
27-32
8
Murayama Y, Nagai A, Okamura K. >et al .
Serum immunoglobulin G antibody to periodontal bacteria.
Adv Dent Res.
1988;
2
339-345
9
Gabay C, Kushner I.
Acute-phase proteins and other systemic responses to inflammation.
N Engl J Med.
1999;
340
448-454
10
Nishimura F, Taniguchi A, Iwamoto Y. >et al .
Porphyromonas gingivalis infection is associated with elevated C-reactive protein
in nonobese Japanese type 2 diabetic subjects.
Diabetes Care.
2002;
25
1888
11
Slade GD, Ghezzi EM, Heiss. >et al .
Relationship between periodontal disease and C-reactive protein among adults in the
Atherosclerosis Risk in Communities study.
Arch Intern Med.
2003;
163
1172-1179
12
Iwamoto Y, Nishimura F, Soga. >et al .
Antimicrobial periodontal treatment decreases serum C-reactive protein, tumor necrosis
factor-alpha, but not adiponectin levels in patients with chronic periodontitis.
J Periodontol.
2003;
74
1231-1236
13
D'Aiuto F, Parkar M, Andreou G. >et al .
Periodontitis and systemic inflammation: control of the local infection is associated
with a reduction in serum inflammatory markers.
J Dent Res.
2004;
83
156-160
14
Iwamoto Y, Nishimura F, Nakagawa M. >et al .
The effect of antimicrobial periodontal treatment on circulating tumor necrosis factor-alpha
and glycated hemoglobin level in patients with type 2 diabetes.
J Periodontol.
2001;
72
774-778
15
Uysal KT, Wiesbrock SM, Marino MW. >et al .
Protection from obesity-induced insulin resistance in mice lacking TNF-alpha function.
Nature.
1997;
389
610-614
16
World Health Organization .
Diabetes Mellitus.
Report of a WHO Study Group. Geneva, World Health Org (Tech. Rep. Ser., no.727)
1985;
17
Friedewald WT, Levy RI, Fredrickson DS.
Estimation of the concentration of low-density lipoprotein cholesterol in plasma,
without use of the preparative ultracentrifuge.
Clin Chem.
1972;
18
499-502
18
Onoue S, Imai T, Kumada H. >et al .
Serum antibodies of periodontitis patients compared to the lipopolysaccharides of
Porphyromonas gingivalis and Fusobacterium nucleatum.
Microbiol Immunol.
2003;
47
51-55
19
Kato A, Ogasawara T, Homma T. >et al .
Lipopolysaccharide-binding protein critically regulates lipopolysaccharide-induced
IFN-beta signaling pathway in human monocytes.
J Immunol.
2004;
172
6185-6194
20
Molvig J, Baek L, Christensen P. >et al .
Endotoxin-stimulated human monocyte secretion of interleukin 1, tumour necrosis factor
alpha, and prostaglandin E2 shows stable interindividual differences.
Scand J Immunol.
1988;
27
705-716
21
Liu S, Gallo DJ, Green AM. >et al .
Role of toll-like receptors in changes in gene expression and NF-kappa B activation
in mouse hepatocytes stimulated with lipopolysaccharide.
Infect Immun.
2002;
70
3433-3442
22
Rattazzi M, Puato M, Faggin E. >et al .
C-reactive protein and interleukin-6 in vascular disease: culprits or passive bystanders?.
J Hypertens.
2003;
21
1787-1803
23
Zwaka TP, Hombach V, Torzewski J.
C-reactive protein-mediated low density lipoprotein uptake by macrophages: implications
for atherosclerosis.
Circulation.
2001;
103
1194-1197
24
Taskinen S, Kovanen PT, Jarva H. >et al .
Binding of C-reactive protein to modified low-density-lipoprotein particles: identification
of cholesterol as a novel ligand for C-reactive protein.
Biochem J.
2002;
367
403-412
25
Feingold KR, Grunfeld C.
Tumor necrosis factor-alpha stimulates hepatic lipogenesis in the rat in vivo .
J Clin Invest.
1987;
80
184-190
26
Memon RA, Grunfeld C, Moser AH. >et al .
Tumor necrosis factor mediates the effects of endotoxin on cholesterol and triglyceride
metabolism in mice.
Endocrinology.
1993;
132
2246-2253
27
Jain A, Batista Jr EL, Serhan C. >et al .
Role for periodontitis in the progression of lipid deposition in an animal model.
Infect Immun.
2003;
71
6012-6018
28
D'Aiuto F, Nibali L, Parker M. et al .
Short-term effects of intensive periodontal therapy on serum inflammatory markers
and cholesterol.
J Dent Res.
2005;
84
269-273
Correspondence
F. NishimuraDDS
Department of Patho-physiology/Periodontal Science·Okayama University·Graduate School
of Medicine·Dentistry and Pharmaceutical Sciences
2-5-1 Shikata-cho·Okayama700-8525·Japan
Phone: +81/86/235 66 76
Fax: +81/86/235 66 79
Email: fusanori@md.okayama-u.ac.jp