Lipopolysaccharide: a Link between Periodontitis and Cardiometabolic Disorders

.................................................................................................................................... 9 1. REVIEW OF THE LITERATURE .............................................................................................. 11 1.1. Periodontal disease ................................................................................................... 11 1.1.1. Structure of the periodontium ..................................................................... 11 1.1.2. Classification of periodontal disease ............................................................ 12 1.1.3. Pathogenesis of periodontitis ....................................................................... 13 1.1.4. Host response ............................................................................................... 14 1.1.5. Genetic susceptibility to periodontitis .......................................................... 17 1.1.6. Definition of periodontitis ............................................................................ 20 1.1.7. Prevention and treatment of chronic periodontitis ..................................... 21 1.2. Lipoprotein metabolism ............................................................................................ 22 1.2.1. Lipoproteins .................................................................................................. 22 1.2.2. Lipoprotein metabolism and lipid transport ................................................. 24 1.3. Lipopolysaccharide .................................................................................................... 26 1.3.1. Structure of LPS............................................................................................. 26 1.3.2. LPS-mediated signaling and the innate immune response .......................... 26 1.3.3. LPS and periodontitis .................................................................................... 27 1.3.4. LPS and nutrition ........................................................................................... 28 1.4. Cardiometabolic disorders ........................................................................................ 29 1.4.1. Atherosclerosis and cardiovascular diseases ................................................ 29 1.4.2. Obesity, metabolic syndrome, and diabetes mellitus .................................. 32 1.5. Periodontitis and cardiometabolic disorders ............................................................ 34 1.5.1. Periodontitis and cardiovascular diseases .................................................... 34 1.5.2. Periodontitis and obesity, MetS, and diabetes ............................................. 37 2. AIMS OF THE STUDY ............................................................................................................ 39 3. STUDY SUBJECTS AND METHODS ....................................................................................... 40 3.1. Study subjects and design ......................................................................................... 40 3.1.1. The Parogene study (I) .................................................................................. 40 3.1.2. The Health 2000 Survey (I) ............................................................................ 40 3.1.3. Periodontitis treatment study in Sweden (II) ............................................... 41 3.1.4. Periodontitis treatment study in Finland (III) ............................................... 41 3.1.5. The FINRISK97 Study (IV) .............................................................................. 41 3.2. Methods .................................................................................................................... 43 3.2.1. Periodontal examination and treatment (I, II, III) ......................................... 44 3.2.2. Genotyping (I) ............................................................................................... 45 3.2.3. Histological analysis and immunohistochemistry (I) .................................... 46 3.2.4. Isolation of lipoproteins (II, III)...................................................................... 46 3.2.5. Serum LPS activity determinations (II, III, IV)................................................ 47 3.2.6. Cell culture (III) .............................................................................................. 47 3.2.7. cDNA synthesis and quantitative real-time PCR (III) .................................... 48 3.2.8. Statistical analysis (I, II, III, IV) ....................................................................... 49 4. RESULTS ............................................................................................................................... 51 4.1. Genetics predisposing to periodontitis (I)................................................................. 51 4.2. Endotoxemia in patients with periodontitis (II, III) ................................................... 54 4.2.1. Plasma LPS activity and lipoprotein distribution in periodontitis patients before and after periodontal treatment (II) ................................... 54 4.2.2. Proatherogenic properties of VLDL isolated from periodontitis patients before and after periodontal treatment (III) ................................................ 55 4.3. Endotoxemia and nutrition in patients with cardiometabolic disorders (IV) ........... 59 5. DISCUSSION ......................................................................................................................... 63 5.1. Genetic basis of periodontitis ................................................................................... 63 5.2. Periodontal parameters and definition of periodontitis .......................................... 64 5.3. Proinflammatory mediators ...................................................................................... 65 5.4. The effects of periodontitis-induced endotoxemia on lipoproteins ......................... 66 5.5. Local and systemic effects of periodontal treatment ............................................... 68 5.6. Endotoxemia, cardiometabolic disorders, and diet .................................................. 69 5.7. Challenges in the determination of LPS activity ....................................................... 70 6. CONCLUSIONS ..................................................................................................................... 72 ACKNOWLEDGEMENTS .............................................................................................................. 75 REFERENCES ............................................................................................................................... 77