- Email: [email protected]
Free fatty acids may be involved in the pathogenesis of oral-related and cardiovascular diseases
Journal of Oral Biosciences ∎ (∎∎∎∎) ∎∎∎–∎∎∎
Contents lists available at ScienceDirect
Journal of Oral Biosciences journal homepage: www.elsevier.com/locate/job
Review
Free fatty acids may be involved in the pathogenesis of oral-related and cardiovascular diseases Yosuke Shikama Department of Oral Disease Research, National Center for Geriatrics and Gerontology, 7-430 Morioka-cho, Obu 474-8511, Japan
art ic l e i nf o
a b s t r a c t
Article history: Received 20 February 2018 Received in revised form 3 April 2018 Accepted 12 April 2018
Background: Adipose tissue insulin resistance plays an important role in the development of type 2 diabetes (T2D) and is characterized by a high rate of lipolysis, resulting in increased plasma free fatty acid (FFA) levels. Among various FFAs, saturated fatty acids (SFAs), such as palmitate (Pal) and stearate, can induce inflammatory responses. Moreover, CD36 (involved in FFA uptake) and its ligands can promote sterile inflammation through the assembly of Toll-like receptor heterodimers. The involvement of these molecules and receptors in the pathogenesis of both oral-related and cardiovascular diseases has been demonstrated. Highlight: SFAs but not unsaturated fatty acids could induce interleukin (IL)-6 production, apoptosis, and α-fodrin degradation in the salivary gland epithelial cells of patients with primary Sjögren's syndrome. High-fat-diet-induced T2D model mice were demonstrated to have a higher expression of CD36 on the surface of gingival fibroblasts. Pal could induce interleukin (IL)-6, IL-8, and CXCL1 secretion in human gingival fibroblasts (HGFs). Porphyromonas gingivalis (P. gingivalis) lipopolysaccharide (LPS) and heatkilled P. gingivalis could augment Pal-induced chemokine secretion in HGFs. Moreover, SFAs were found to increase IL-1β secretion and decrease IL-1 receptor antagonist (IL-1Ra) secretion in human monocytes, resulting in an increase in the IL-1β/IL-1Ra secretion ratio. This could induce the expression and release of adhesion molecules, such as intercellular adhesion molecule-1 (ICAM-1) and E-selectin, in human aortic and vein endothelial cells. Conclusion: In this review, we summarize a potential link between FFAs and the pathogenesis of craniofacial and cardiovascular diseases. & 2018 Published by Elsevier B.V. on behalf of Japanese Association for Oral Biology.
Keywords: Periodontitis Free fatty acid Metabolic disorder Salivary gland Cardiovascular disease
1. Introduction Obesity is a global health issue that affects the morbidity and mortality of metabolic diseases. In comparison with normal-weight people, overweight or obese people have a more than 10-fold risk of developing type 2 diabetes (T2D) [1]. The level of free fatty acids (FFAs) in the blood is elevated in obese individuals and patients with T2D as well as in the corresponding animal models [2], which may be attributed to augmented lipolysis in adipocytes and increased dietary fat intake [3]. Among various FFAs, saturated fatty acids (SFAs), such as palmitate (Pal) and stearate, can induce pro-inflammatory responses mainly via the Toll-like receptor (TLR) signaling pathway [4,5]. Pal also induces diacylglycerol and ceramide accumulation [6,7], stress kinase activation [8,9], endoplasmic reticulum stress [10], mitochondrial reactive species production [9], and apoptosis [11]. In contrast, unsaturated fatty acids (UFAs), such as oleate, have little or no effect on these processes and can even prevent the stress or toxic
effects of Pal [7,9–11]. Notably, methyl palmitate and 2-bromopalmitic acid (a non-metabolizable analog of Pal) do not induce pro-inflammatory cytokines, suggesting that Pal metabolism via the glycerolipid biosynthetic pathway, ceramide biosynthetic pathway, or β-oxidation pathway is necessary for the induction of these cytokines [12]. A high intake of SFAs has been linked to a higher risk of T2D and coronary artery disease [13]. Furthermore, fatty acid translocase (also known as CD36) is involved in FFA uptake [14], and CD36 ligands facilitate sterile inflammation through the assembly of TLR heterodimers [15]. Increased plasma FFAs can elicit pro-inflammatory responses by intracellular lipid accumulation, potentially leading to so-called “lipotoxicity.” Lipotoxicity has been observed in pancreatic β-cells, hepatocytes, cardiomyocytes, and skeletal muscle cells [16]; however, it is rarely reported for epithelial cells. Clinical and epidemiological studies have demonstrated that metabolic disorders, including obesity and diabetes, are a risk factor for periodontitis [17–19] and primary Sjögren's syndrome
Abbreviations: FFAs, free fatty acids; HGFs, human gingival fibroblasts; Pal, palmitate; SFAs, saturated fatty acids; SS, Sjögren's syndrome; T2D, type 2 diabetes; UFAs, unsaturated fatty acids E-mail address: [email protected] https://doi.org/10.1016/j.job.2018.04.001 1349-0079/& 2018 Published by Elsevier B.V. on behalf of Japanese Association for Oral Biology.
Please cite this article as: Shikama Y. Free fatty acids may be involved in the pathogenesis of oral-related and cardiovascular diseases. J Oral Biosci (2018), https://doi.org/10.1016/j.job.2018.04.001i
2
Y. Shikama / Journal of Oral Biosciences ∎ (∎∎∎∎) ∎∎∎–∎∎∎
(SS) [20,21]. However, the clinical significance of SFAs in terms of onset and pathogenesis is unknown. Although a recent study investigated the direct effects of SFAs on inflammatory responses in vascular endothelial cells [4], it remains unclear whether SFAs can also induce these responses mediated by circulating cells. In this review, we highlight recent findings on the potential involvement of Pal in the pathogenesis of periodontitis, primary SS, and cardiovascular diseases. In addition, we discuss the potential of lipid profile improvement as a new strategy for the treatment of these diseases.
2. Potential role of Pal in the pathogenesis of primary SS Primary SS is an autoimmune disorder characterized by the chronic dysfunction and destruction of exocrine glands (mainly the salivary and lacrimal glands) due to lesions chronically infiltrated by lymphocytes. This leads to persistent dryness of the eyes and mouth. Salivary gland epithelial cells are known to play an important role as a trigger for the development of SS. For example, IL-6 is up-regulated in the ductal epithelial cells of salivary glands in patients with primary SS. Furthermore, the extent and intensity of IL-6 expression in epithelial cells are correlated with the grade of mononuclear cell infiltration [22]. α-Fodrin is a ubiquitous, heterodimeric calmodulin-binding protein that is cleaved during apoptosis by caspase-3 or μ-calpain. In addition to the ribonucleoprotein particles SS-A/Ro and SS-B/La [23], a 120-kDa fragment derived from α-fodrin has been reported to act as an auto-antigen in patients with primary SS [24]. Although the molecular mechanisms underlying the relationship between metabolic disorders and SS are largely unclear, we previously demonstrated that Pal can induce IL-6 secretion and α-fodrin cleavage in salivary gland epithelial cell lines, suggesting a possible link between the pathogenesis of primary SS and Pal level in the blood [25]. Some studies have reported the beneficial effects of lipid-related molecules on the salivary glands both in vivo and in vitro. Leigh et al. [26] found that a biosynthetic pathway of resolvin D1, a derivative of docosahexaenoic acid (DHA; an omega-3 polyunsaturated fatty acid), exists in murine and human salivary gland cells, and the distribution of resolvin D1 biosynthesis-related mediators in the salivary gland cells of healthy subjects and patients with SS is different, suggesting that resolvin D1 is produced but not delivered to target cells in the salivary glands of patients with SS. Resolvin D1 also blocks inflammation mediated by tumor necrosis factor-α (TNF-α), which is an inflammatory cytokine that can induce apoptosis in salivary gland cells [27], and increases the barrier function and cell polarity of salivary gland cells [28,29]. These findings suggest that DHA supplementation has preventive and therapeutic effects on inflammatory diseases of the salivary glands, such as SS.
3. Potential role of Pal in the pathogenesis of periodontitis Periodontitis is characterized by the inflammatory destruction of periodontal tissues due to uncontrolled, detrimental bacteria-host interactions in susceptible individuals [30]. In periodontal lesions, gingival fibroblasts and epithelial cells play an active role in host defense, releasing a variety of pro-inflammatory mediators such as IL-6, IL-8, and GROα/CXCL1 [31,32]. We previously reported the expression of CD36 on the surface of gingival fibroblasts, which was increased for the gingival fibroblasts of high-fat-diet-induced T2D mice compared with those of mice fed a normal diet. We found that Pal induced IL-6, IL-8, and CXCL1 secretion in HGFs, and DHA suppressed Pal-induced IL-6 and IL-8 production. The treatment of HGFs with a CD36 inhibitor also inhibited Pal-induced pro-inflammatory responses. Furthermore, we demonstrated that P. gingivalis LPS and
heat-killed P. gingivalis augmented Pal-induced chemokine secretion in HGFs [33] (Fig. 1). A study has reported that Pal exhibits inflammatory potential accelerating alveolar bone loss in an experimental periodontal disease model in obese mice and affecting the pro-inflammatory osteoclastic response to P. gingivalis infection in vitro [34]. LPS derived from Aggregatibacter actinomycetemcomitans has also been found to augment high-fat-diet-induced CD36 expression in periodontal tissues [35]. In addition to their role in the pathogenesis of periodontitis, P. gingivalis and P. gingivalis LPS could augment high-fat-diet-induced and Pal-induced endothelial injury [36] and steatohepatitis [37]. These results suggest a potential link between plasma FFAs and the pathogenesis of periodontitis. Recent studies have demonstrated that lipid-related molecules may improve the condition of patients with periodontitis. For example, DHA supplementation was reported to improve the periodontal condition of patients with periodontitis [38], and resolvin D1 was found to decrease P. gingivalis-induced chemokine secretion in HGFs [39]. Moreover, resolvin E1, a lipid mediator derived from eicosapentaenoic acid (EPA), can protect against local inflammation and osteoclast-mediated bone destruction in periodontitis [40]. In agreement with these findings, a study found that the ratio of n3 (antiinflammatory) to n6 (pro-inflammatory) polyunsaturated fatty acids, i.e., (DHA þ EPA)/arachidonic acid, was significantly lower in the gingival crevicular fluid of patients with aggressive periodontitis [41].
4. Potential role of Pal in the pathogenesis of cardiovascular diseases The molecular mechanisms of vascular inflammation and atherosclerosis have been extensively studied, and the crucial role of vascular endothelial cell adhesion molecules, such as ICAM-1 and E-selectin, in the interaction between leukocytes and the vascular endothelium has been established. The expression of these adhesion molecules facilitates the binding of leukocytes to the activated endothelium, which is critical for the pathogenesis of cardiovascular diseases [42,43]. The IL-1 signaling pathway is important for inducing the expression and release of adhesion molecules in vascular endothelial cells [44,45]. IL-1β, a prototypic pro-inflammatory cytokine, also plays a crucial role in the pathogenesis of T2D [46] and cardiovascular diseases [47]. Mouse models of atherosclerosis have demonstrated the pro-atherogenic properties of IL-1β associated with the up-regulation of endothelial adhesion molecules, which are responsible for monocyte adhesion and migration [48,49]. IL-1Ra is another member of the IL-1 family that can bind to IL-1 receptors without signal transduction, acting as a naturally occurring antagonist. The production of IL-1β and IL-1Ra in monocytes is differentially regulated [50,51], and their secretion ratio (IL-1β/IL-1Ra; designated as ‘β/Ra') is crucial for vascular inflammation and atherosclerosis [48,49,52]. Moreover, a recent study has demonstrated the essential role of IL-1β signaling in the formation of experimental abdominal aortic aneurysm, which could be attenuated by recombinant IL-1Ra (anakinra) supplementation [53], thus indicating the protective effects of IL-1Ra supplementation against vascular inflammation and atherosclerosis. Although Pal has been reported to induce IL-1β secretion in human monocytes [5], little is known about the effects of Pal on IL-1Ra secretion in human monocytes or the effects of Pal-induced secretion on adhesion molecule expression in vascular endothelial cells. Therefore, we have examined the indirect effects of Pal on the expression and release of ICAM-1 and E-selectin in vascular endothelial cells. SFAs but not UFAs were found to increase IL-1β secretion and decrease L-1Ra secretion, resulting in an increase in the β/Ra secretion ratio. UFAs dose-dependently inhibited the increase in IL-1β secretion and the decrease in IL-1Ra secretion
Please cite this article as: Shikama Y. Free fatty acids may be involved in the pathogenesis of oral-related and cardiovascular diseases. J Oral Biosci (2018), https://doi.org/10.1016/j.job.2018.04.001i
Y. Shikama / Journal of Oral Biosciences ∎ (∎∎∎∎) ∎∎∎–∎∎∎
Pal
3
Pal
TLRs
TLRs CD36
CD36
HGF
HGF IL-8 CXCL1
IL-6 IL-8 CXCL1
Monocytes/Neutrophils Monocytes/Neutrophils Fig. 1. Potential mechanism of the involvement of Pal in the pathogenesis of periodontitis. Left panel: Pal induces IL-6, IL-8, and CXCL1 production in HGFs. Right panel: Pal augments P. gingivalis-induced IL-8 and CXCL1 production in HGFs, resulting in the accumulation of monocytes and neutrophils in periodontal tissues.
A) Normal Vascular endothelial cells
IL-1
Monocytes
IL-1Ra
IL-1R1
Promotes plaque formation
B) SFA-rich condition in plasma
Pal
IL-1Ra Rolling
IL-1
Firm adhesion
/Ra IL-1R1 E-selectin
ICAM-1
Facilitates trans-endothelial migration of leukocytes
Fig. 2. Potential mechanism of the involvement of Pal in the pathogenesis of cardiovascular diseases. A) Under healthy conditions, the expression of adhesion molecules (ICAM-1 and E-selectin) is low in vascular endothelial cells because β/Ra is well balanced in the plasma. B) Under SFA-rich conditions, Pal increases IL-1β production and decreases IL-1Ra production in monocytes, resulting in an increase in β/Ra in the plasma. This induces the expression of adhesion molecules mediated by IL-1 receptor 1 (IL1R1) signaling in vascular endothelial cells, promoting plaque formation and facilitating the trans-endothelial migration of leukocytes.
induced by Pal. Moreover, in human aortic and vein endothelial cells, the expression and release of ICAM-1 and E-selectin were induced by treatment with conditioned medium collected from Pal-stimulated human monocytes but not by treatment with Pal only. The up-regulated expression and release of adhesion molecules by the conditioned medium were mostly abolished by recombinant human IL-1Ra supplementation. These results suggest that the Pal-induced increase in the ratio of β/Ra secretion in monocytes can up-regulate endothelial adhesion molecules, which may enhance leukocyte adhesion to the endothelium [54] (Fig. 2). In rodent models, IL-1Ra-deficient mice were reported to exhibit impaired lipid metabolism following high-fat-diet-induced
inflammation [55], and IL-1Ra administration was found to reduce hyperglycemia and tissue inflammation in T2D GK rats [56]. Moreover, preclinical and clinical trial results have indicated that IL-1β blockage may be beneficial for patients who have or are at risk of cardiovascular diseases [57]. The findings partly demonstrate the clinical significance of IL-1Ra treatment in cardiovascular diseases.
5. Conclusion Our study has revealed the importance of FFAs in the pathogenesis of oral-related and cardiovascular diseases. According to
Please cite this article as: Shikama Y. Free fatty acids may be involved in the pathogenesis of oral-related and cardiovascular diseases. J Oral Biosci (2018), https://doi.org/10.1016/j.job.2018.04.001i
Y. Shikama / Journal of Oral Biosciences ∎ (∎∎∎∎) ∎∎∎–∎∎∎
4
our current results and those of previous studies, supplementation with polyunsaturated fatty acids or these derivatives may be beneficial for the treatment of primary SS, periodontitis, and cardiovascular diseases. Nevertheless, further research on the association between lipid-related molecules and the pathogenesis of these diseases is needed to develop novel therapeutic strategies.
Acknowledgments The author would like to thank Yasusei Kudo, Naozumi Ishimaru (Tokushima University, Japan), and Makoto Funaki (Tokushima University Hospital, Japan) for the experimental studies discussed in this review.
[13] [14]
[15]
[16] [17]
[18] [19] [20]
Ethical approval
[21]
This review did not require ethical approval. [22]
Conflict of interest The authors declare no conflict of interest.
Funding This study was supported in part by a Grant-in-Aid for Research Activity Start-up from the Ministry of Education, Culture, Sports, Science and Technology (16H07017 to Y.S.) and Research Funding for Longevity Sciences (29-19 to Y.S.) from the National Center for Geriatrics and Gerontology (NCGG), Japan.
[23]
[24]
[25]
[26] [27]
[28]
References [29] [1] Kopelman P. Health risks associated with overweight and obesity. Obes Rev 2007;8:13–7. [2] Boden G. Interaction between free fatty acids and glucose metabolism. Curr Opin Clin Nutr Metab Care 2002;5:545–9. [3] Cnop M. Fatty acids and glucolipotoxicity in the pathogenesis of type 2 diabetes. Biochem Trans 2008;36:348–52. [4] Maloney E, Sweet IR, Hockenbery DM, Pham M, Rizzo NO, Tateya S, Handa P, Schwartz MW, Kim F. Activation of NF-κB by palmitate in endothelial cells: a key role for NADPH oxidase-derived superoxide in response to TLR4 activation. ArteriosclerThrombVasc Biol 2009;29:1370–5. [5] Snodgrass RG, Huang S, Choi IW, Rutledge JC, Hwang DH. Inflammasomemediated secretion of IL-1β in human monocytes through TLR2 activation; modulation by dietary fatty acids. J Immunol 2013;191:4337–47. [6] Chavez JA, Summers SA. Characterizing the effects of saturated fatty acids on insulin signaling and ceramide and diacylglycerol accumulation in 3T3-L1 adipocytes and C2C12 myotubes. Arch Biochem 2003;419:101–9. [7] Coll T, Eyre E, Rodriguez-Calvo R, Palomer X, Sanchez RM, Merlos M, Laguna JC, Vazquez-Carrera M. Oleate reverses palmitate-induced insulin resistance and inflammation in skeletal muscle cells. J Biol Chem 2008;283:11107–16. [8] Sinha S, Perdomo G, Brown NF, O'Doherty RM. Fatty acid-induced insulin resistance in L6 myotubes is prevented by inhibition of activation and nuclear localization of nuclear factor kappa B. J Biol Chem 2004;279:41294–301. [9] Yuzefovych L, Wilson G, Rachek L. Different effects of oleate vs. palmitate on mitochondrial function, apoptosis, and insulin signaling in L6 skeletal muscle cells: role of oxidative stress. Am J Physiol Endocrinol Metab 2010;299:E1096–105. [10] Peng G, Li L, Liu Y, Pu J, Zhang S, Yu J, Zhao J, Liu P. Oleate blocks palmitateinduced abnormal lipid distribution, endoplasmic reticulum expansion and stress, and insulin resistance in skeletal muscle. Endocrinology 2011;152:2206–18. [11] Turpin SM, Lancaster GI, Darby I, Febbraio MA, Watt MJ. Apoptosis in skeletal muscle myotubes is induced by ceramides and is positively related to insulin resistance. Am J Physiol Endocrinol Metab 2006;291:E1341–50. [12] Bunn RC, Cockrell GE, Ou Y, Thrailkill KM, Lumpkin Jr CK, Fowlkes JL. Palmitate
[30] [31]
[32]
[33] [34]
[35]
[36]
[37]
[38]
[39]
and insulin synergistically induce IL-6 expression in human monocytes. Cardiovasc Diabetol 2010;9:73. Riserus U, Willett WC, Hu FB. Dietary fats and prevention of type 2 diabetes. Prog Lipid Res 2009;48:44–51. Campbell SE, Tandon NN, Woldegiorgis G, Luiken JJ, Glatz JF, Bonen A. A novel function for fatty acid translocase (FAT)/CD36: involvement in long chain fatty acid transfer into the mitochondria. J Biol Chem 2004;279:36235–41. Stewart CR, Stuart LM, Wilkinson K, van Gils JM, Deng J, Halle A, Rayner KJ, Boyer L, Zhong R, Frazier WA, Lacy-Hulbert A, El Khoury J, Golenbock DT, Moore KJ. CD36 ligands promote sterile inflammation through assembly of a Toll-like receptor 4 and 6 heterodimer. Nat Immunol 2010;11:155–61. Kusminski CM, Shetty S, Orci L, Unger RH, Scherer PE. Diabetes and apoptosis: lipotoxicity. Apoptosis 2009;14:1484–95. Nelson RG, Shlossman M, Budding LM, Pettitt DJ, Saad MF, Genco RJ, Knowler WC. Periodontal disease and NIDDM in Pima Indians. Diabetes Care 1990;13:836–40. Saito T, Shimazaki Y, Sakamoto M. Obesity and periodontitis. N Engl J Med 1998;339:482–3. Tervonen T, Karjalainen K, Knuuttila M, Huumonen S. Alveolar bone loss in type 1 diabetic subjects. J Clin Periodontol 2000;27:567–71. Kang JH, Lin HC. Comorbidities in patients with primary Sjögren's syndrome: a registry-based case-control study. J Rheumatol 2010;37:1188–94. Ramos-Casals M, Brito-Zeron P, Siso A, Vargas A, Ros E, Bove A, Belenguer R, Plaza J, Benavent J, Font J. High prevalence of serum metabolic alterations in primary Sjögren's syndrome: influence on clinical and immunological expression. J Rheumatol 2007;34:754–61. Sekiguchi M, Iwasaki T, Kitano M, Kuno H, Hashimoto N, Kawahito Y, Azuma M, Hla T, Sano H. Role of sphingosine 1-phosphate in the pathogenesis of Sjögren's syndrome. J Immunol 2008;180:1921–8. Chan EK, Hamel JC, Buyon JP, Tan EM. Molecular definition and sequence motifs of the 52-kD component of human SS-A/Ro autoantigen. J Clin Invest 1991;87:68–76. Haneji N, Nakamura T, Takio K, Yanagi K, Higashiyama H, Saito I, Noji S, Sugino H, Hayashi Y. Identification of α-fodrin as a candidate autoantigen in primary Sjögren's syndrome. Science 1997;276:604–7. Shikama Y, Ishimaru N, Kudo Y, Bando Y, Aki N, Hayashi Y, Funaki M. Effects of free fatty acids on human salivary gland epithelial cells. J Dent Res 2013;92:540–6. Leigh NJ, Nelson JW, Mellas RE, Aguirre A, Baker OJ. Expression of resolvin D1 biosynthetic pathways in salivary epithelium. J Dent Res 2014;93:300–5. Azuma M, Aota K, Tamatani T, Motegi K, Yamashita T, Harada K, Hayashi Y, Sato M. Suppression of tumor necrosis factor α-induced matrix metalloproteinase 9 production by the introduction of a super-repressor form of inhibitor of nuclear factor κBα complementary DNA into immortalized human salivary gland acinar cells: prevention of the destruction of the acinar structure in Sjögren's syndrome salivary glands. Arthritis Rheum 2000;43:1756–67. Nelson JW, Leigh NJ, Mellas RE, McCall AD, Aguirre A, Baker OJ. ALX/FPR2 receptor for RvD1 is expressed and functional in salivary glands. Am J Physiol Cell Physiol 2014;306:C178–85. Odusanwo O, Chinthamani S, McCall A, Duffey ME, Baker OJ. Resolvin D1 prevents TNF-α-mediated disruption of salivary epithelial formation. Am J Physiol Cell Physiol 2012;302:C1331–45. Darveau RP. Periodontitis: a polymicrobial disruption of host homeostasis. Nat Rev Microbiol 2010;8:481–90. Almasri A, Wisithphrom K, Windsor LJ, Olson B. Nicotine and lipopolysaccharide affect cytokine expression from gingival fibroblasts. J Periodontol 2007;78:533–41. Kusumoto Y, Hirano H, Saitoh K, Yamada S, Takedachi M, Nozaki T, Ozawa Y, Nakahira Y, Saho T, Ogo H, Shimabukuro Y, Okada H, Murakami S. Human gingival epithelial cells produce chemotactic factors interleukin-8 and monocyte chemoattractant protein-1 after stimulation with Porphyromonasgingivalis via toll-like receptor 2. J Periodontol 2004;75:370–9. Shikama Y, Kudo Y, Ishimaru N, Funaki M. Possible involvement of palmitate in pathogenesis of periodontitis. J Cell Physiol 2015;230:2981–9. Muluke M, Gold T, Kiefhaber K, Al-Sahli A, Celenti R, Jiang H, Cremers S, Van Dyke T, Schulze-Spate U. Diet-induced obesity and its differential impact on periodontal bone loss. J Dent Res 2016;95:223–9. Lu Z, Li Y, Brinson CW, Kirkwood KL, Lopes-Virella MF, Huang Y. CD36 is upregulated in mice with periodontitis and metabolic syndrome and involved in macrophage gene upregulation by palmitate. Oral Dis 2017;23:210–8. Ao M, Miyauchi M, Inubushi T, Kitagawa M, Furusho H, Ando T, Ayuningtyas NF, Nagasaki A, Ishihara K, Tahara H, Kozai K, Takata T. Infection with Porphyromonasgingivalis exacerbates endothelial injury in obese mice. PLoS One 2014;9:e110519. Furusho H, Miyauchi M, Hyogo H, Inubushi T, Ao M, Ouhara K, Hisatune J, Kurihara H, Sugai M, Hayes CN, Nakahara T, Aikata H, Takahashi S, Chayama K, Takata T. Dental infection of Porphyromonasgingivalis exacerbates high fat diet-induced steatohepatitis in mice. J Gastroenterol 2013;48:1259–70. Naqvi AZ, Hasturk H, Mu L, Phillips RS, Davis RB, Halem S, Campos H, Goodson JM, Van Dyke TE, Mukamal KJ. Docosahexaenoic acid and periodontitis in adults: a randomized controlled trial. J Dent Res 2014;93:767–73. Khaled M, Shibani NA, Labban N, Batarseh G, Song F, Ruby J, Windsor LJ. Effects of resolvin D1 on cell survival and cytokine expression of human gingival
Please cite this article as: Shikama Y. Free fatty acids may be involved in the pathogenesis of oral-related and cardiovascular diseases. J Oral Biosci (2018), https://doi.org/10.1016/j.job.2018.04.001i
Y. Shikama / Journal of Oral Biosciences ∎ (∎∎∎∎) ∎∎∎–∎∎∎ fibroblasts. J Periodontol 2013;84:1838–46. [40] Hasturk H, Kantarci A, Ohira T, Arita M, Ebrahimi N, Chiang N, Petasis NA, Levy BD, Serhan CN, Van Dyke TE. RvE1 protects from local inflammation and osteoclast- mediated bone destruction in periodontitis. FASEB J 2006;20:401–3. [41] Elabdeen HR, Mustafa M, Szklenar M, Ruhl R, Ali R, Bolstad AI. Ratio of proresolving and pro-inflammatory lipid mediator precursors as potential markers for aggressive periodontitis. PLoS One 2013;8:e70838. [42] Springer TA. Traffic signals for lymphocyte recirculation and leukocyte emigration: the multistep paradigm. Cell 1994;76:301–14. [43] Woollard KJ, Geissmann F. Monocytes in atherosclerosis: subsets and functions. Nat Rev Cardiol 2010;7:77–86. [44] Haraldsen G, Kvale D, Lien B, Farstad IN, Brandtzaeg P. Cytokine-regulated expression of E-selectin, intercellular adhesion molecule-1 (ICAM-1), and vascular cell adhesion molecule-1 (VCAM-1) in human microvascular endothelial cells. J Immunol 1996;156:2558–65. [45] Szekanecz Z, Shah MR, Pearce WH, Koch AE. Intercellular adhesion molecule-1 (ICAM-1) expression and soluble ICAM-1 (sICAM-1) production by cytokineactivated human aortic endothelial cells: a possible role for ICAM-1 and sICAM-1 in atherosclerotic aortic aneurysms. Clin Exp Immunol 1994;98:337–43. [46] Maedler K, Sergeev P, Ris F, Oberholzer J, Joller-Jemelka HI, Spinas GA, Kaiser N, Halban PA, Donath MY. Glucose-induced β cell production of IL-1β contributes to glucotoxicity in human pancreatic islets. J Clin Invest 2002;110:851–60. [47] von der Thusen JH, Kuiper J, van Berkel TJ, Biessen EA. Interleukins in atherosclerosis: molecular pathways and therapeutic potential. Pharmacol Rev 2003;55:133–66. [48] Kirii H, Niwa T, Yamada Y, Wada H, Saito K, Iwakura Y, Asano M, Moriwaki H, Seishima M. Lack of interleukin-1β decreases the severity of atherosclerosis in ApoE-deficient mice. ArteriosclerThromb Vasc Biol 2003;23:656–60.
5
[49] Takahashi M, Ikeda U, Masuyama J, Kitagawa S, Kasahara T, Shimpo M, Kano S, Shimada K. Monocyte-endothelial cell interaction induces expression of adhesion molecules on human umbilical cord endothelial cells. Cardiovasc Res 1996;32:422–9. [50] Arend WP, Smith Jr MF, Janson RW, Joslin FG. IL-1 receptor antagonist and IL-1 beta production in human monocytes are regulated differently. J Immunol 1991;147:1530–6. [51] Poutsiaka DD, Clark BD, Vannier E, Dinarello CA. Production of interleukin-1 receptor antagonist and interleukin-1 beta by peripheral blood mononuclear cells is differentially regulated. Blood 1991;78:1275–81. [52] Arend WP. The balance between IL-1 and IL-1Ra in disease. Cytokine Growth Factor Rev 2002;13:323–40. [53] Johnston WF, Salmon M, Su G, Lu G, Stone ML, Zhao Y, Owens GK, Upchurch Jr GR, Ailawadi G. Genetic and pharmacologic disruption of interleukin-1β signaling inhibits experimental aortic aneurysm formation. ArteriosclerThromb Vasc Biol 2013;33:294–304. [54] Shikama Y, Aki N, Hata A, Nishimura M, Oyadomari S, Funaki M. Palmitatestimulated monocytes induce adhesion molecule expression in endothelial cells via IL-1 signaling pathway. J Cell Physiol 2015;230:732–42. [55] Isoda K, Sawada S, Ayaori M, Matsuki T, Horai R, Kagata Y, Miyazaki K, Kusuhara M, Okazaki M, Matsubara O, Iwakura Y, Ohsuzu F. Deficiency of interleukin-1 receptor antagonist deteriorates fatty liver and cholesterol metabolism in hypercholesterolemic mice. J Biol Chem 2005;280: 7002–7009. [56] Ehses JA, Lacraz G, Giroix MH, Schmidlin F, Coulaud J, Kassis N, Irminger JC, Kergoat M, Portha B, Homo-Delarche F, Donath MY. IL-1 antagonism reduces hyperglycemia and tissue inflammation in the type 2 diabetic GK rat. Proc Natl Acad Sci USA 2009;106:13998–4003. [57] Van Tassell BW, Toldo S, Mezzaroma E, Abbate A. Targeting interleukin-1 in heart disease. Circulation 2013;128:1910–23.
Please cite this article as: Shikama Y. Free fatty acids may be involved in the pathogenesis of oral-related and cardiovascular diseases. J Oral Biosci (2018), https://doi.org/10.1016/j.job.2018.04.001i
Contents lists available at ScienceDirect
Journal of Oral Biosciences journal homepage: www.elsevier.com/locate/job
Review
Free fatty acids may be involved in the pathogenesis of oral-related and cardiovascular diseases Yosuke Shikama Department of Oral Disease Research, National Center for Geriatrics and Gerontology, 7-430 Morioka-cho, Obu 474-8511, Japan
art ic l e i nf o
a b s t r a c t
Article history: Received 20 February 2018 Received in revised form 3 April 2018 Accepted 12 April 2018
Background: Adipose tissue insulin resistance plays an important role in the development of type 2 diabetes (T2D) and is characterized by a high rate of lipolysis, resulting in increased plasma free fatty acid (FFA) levels. Among various FFAs, saturated fatty acids (SFAs), such as palmitate (Pal) and stearate, can induce inflammatory responses. Moreover, CD36 (involved in FFA uptake) and its ligands can promote sterile inflammation through the assembly of Toll-like receptor heterodimers. The involvement of these molecules and receptors in the pathogenesis of both oral-related and cardiovascular diseases has been demonstrated. Highlight: SFAs but not unsaturated fatty acids could induce interleukin (IL)-6 production, apoptosis, and α-fodrin degradation in the salivary gland epithelial cells of patients with primary Sjögren's syndrome. High-fat-diet-induced T2D model mice were demonstrated to have a higher expression of CD36 on the surface of gingival fibroblasts. Pal could induce interleukin (IL)-6, IL-8, and CXCL1 secretion in human gingival fibroblasts (HGFs). Porphyromonas gingivalis (P. gingivalis) lipopolysaccharide (LPS) and heatkilled P. gingivalis could augment Pal-induced chemokine secretion in HGFs. Moreover, SFAs were found to increase IL-1β secretion and decrease IL-1 receptor antagonist (IL-1Ra) secretion in human monocytes, resulting in an increase in the IL-1β/IL-1Ra secretion ratio. This could induce the expression and release of adhesion molecules, such as intercellular adhesion molecule-1 (ICAM-1) and E-selectin, in human aortic and vein endothelial cells. Conclusion: In this review, we summarize a potential link between FFAs and the pathogenesis of craniofacial and cardiovascular diseases. & 2018 Published by Elsevier B.V. on behalf of Japanese Association for Oral Biology.
Keywords: Periodontitis Free fatty acid Metabolic disorder Salivary gland Cardiovascular disease
1. Introduction Obesity is a global health issue that affects the morbidity and mortality of metabolic diseases. In comparison with normal-weight people, overweight or obese people have a more than 10-fold risk of developing type 2 diabetes (T2D) [1]. The level of free fatty acids (FFAs) in the blood is elevated in obese individuals and patients with T2D as well as in the corresponding animal models [2], which may be attributed to augmented lipolysis in adipocytes and increased dietary fat intake [3]. Among various FFAs, saturated fatty acids (SFAs), such as palmitate (Pal) and stearate, can induce pro-inflammatory responses mainly via the Toll-like receptor (TLR) signaling pathway [4,5]. Pal also induces diacylglycerol and ceramide accumulation [6,7], stress kinase activation [8,9], endoplasmic reticulum stress [10], mitochondrial reactive species production [9], and apoptosis [11]. In contrast, unsaturated fatty acids (UFAs), such as oleate, have little or no effect on these processes and can even prevent the stress or toxic
effects of Pal [7,9–11]. Notably, methyl palmitate and 2-bromopalmitic acid (a non-metabolizable analog of Pal) do not induce pro-inflammatory cytokines, suggesting that Pal metabolism via the glycerolipid biosynthetic pathway, ceramide biosynthetic pathway, or β-oxidation pathway is necessary for the induction of these cytokines [12]. A high intake of SFAs has been linked to a higher risk of T2D and coronary artery disease [13]. Furthermore, fatty acid translocase (also known as CD36) is involved in FFA uptake [14], and CD36 ligands facilitate sterile inflammation through the assembly of TLR heterodimers [15]. Increased plasma FFAs can elicit pro-inflammatory responses by intracellular lipid accumulation, potentially leading to so-called “lipotoxicity.” Lipotoxicity has been observed in pancreatic β-cells, hepatocytes, cardiomyocytes, and skeletal muscle cells [16]; however, it is rarely reported for epithelial cells. Clinical and epidemiological studies have demonstrated that metabolic disorders, including obesity and diabetes, are a risk factor for periodontitis [17–19] and primary Sjögren's syndrome
Abbreviations: FFAs, free fatty acids; HGFs, human gingival fibroblasts; Pal, palmitate; SFAs, saturated fatty acids; SS, Sjögren's syndrome; T2D, type 2 diabetes; UFAs, unsaturated fatty acids E-mail address: [email protected] https://doi.org/10.1016/j.job.2018.04.001 1349-0079/& 2018 Published by Elsevier B.V. on behalf of Japanese Association for Oral Biology.
Please cite this article as: Shikama Y. Free fatty acids may be involved in the pathogenesis of oral-related and cardiovascular diseases. J Oral Biosci (2018), https://doi.org/10.1016/j.job.2018.04.001i
2
Y. Shikama / Journal of Oral Biosciences ∎ (∎∎∎∎) ∎∎∎–∎∎∎
(SS) [20,21]. However, the clinical significance of SFAs in terms of onset and pathogenesis is unknown. Although a recent study investigated the direct effects of SFAs on inflammatory responses in vascular endothelial cells [4], it remains unclear whether SFAs can also induce these responses mediated by circulating cells. In this review, we highlight recent findings on the potential involvement of Pal in the pathogenesis of periodontitis, primary SS, and cardiovascular diseases. In addition, we discuss the potential of lipid profile improvement as a new strategy for the treatment of these diseases.
2. Potential role of Pal in the pathogenesis of primary SS Primary SS is an autoimmune disorder characterized by the chronic dysfunction and destruction of exocrine glands (mainly the salivary and lacrimal glands) due to lesions chronically infiltrated by lymphocytes. This leads to persistent dryness of the eyes and mouth. Salivary gland epithelial cells are known to play an important role as a trigger for the development of SS. For example, IL-6 is up-regulated in the ductal epithelial cells of salivary glands in patients with primary SS. Furthermore, the extent and intensity of IL-6 expression in epithelial cells are correlated with the grade of mononuclear cell infiltration [22]. α-Fodrin is a ubiquitous, heterodimeric calmodulin-binding protein that is cleaved during apoptosis by caspase-3 or μ-calpain. In addition to the ribonucleoprotein particles SS-A/Ro and SS-B/La [23], a 120-kDa fragment derived from α-fodrin has been reported to act as an auto-antigen in patients with primary SS [24]. Although the molecular mechanisms underlying the relationship between metabolic disorders and SS are largely unclear, we previously demonstrated that Pal can induce IL-6 secretion and α-fodrin cleavage in salivary gland epithelial cell lines, suggesting a possible link between the pathogenesis of primary SS and Pal level in the blood [25]. Some studies have reported the beneficial effects of lipid-related molecules on the salivary glands both in vivo and in vitro. Leigh et al. [26] found that a biosynthetic pathway of resolvin D1, a derivative of docosahexaenoic acid (DHA; an omega-3 polyunsaturated fatty acid), exists in murine and human salivary gland cells, and the distribution of resolvin D1 biosynthesis-related mediators in the salivary gland cells of healthy subjects and patients with SS is different, suggesting that resolvin D1 is produced but not delivered to target cells in the salivary glands of patients with SS. Resolvin D1 also blocks inflammation mediated by tumor necrosis factor-α (TNF-α), which is an inflammatory cytokine that can induce apoptosis in salivary gland cells [27], and increases the barrier function and cell polarity of salivary gland cells [28,29]. These findings suggest that DHA supplementation has preventive and therapeutic effects on inflammatory diseases of the salivary glands, such as SS.
3. Potential role of Pal in the pathogenesis of periodontitis Periodontitis is characterized by the inflammatory destruction of periodontal tissues due to uncontrolled, detrimental bacteria-host interactions in susceptible individuals [30]. In periodontal lesions, gingival fibroblasts and epithelial cells play an active role in host defense, releasing a variety of pro-inflammatory mediators such as IL-6, IL-8, and GROα/CXCL1 [31,32]. We previously reported the expression of CD36 on the surface of gingival fibroblasts, which was increased for the gingival fibroblasts of high-fat-diet-induced T2D mice compared with those of mice fed a normal diet. We found that Pal induced IL-6, IL-8, and CXCL1 secretion in HGFs, and DHA suppressed Pal-induced IL-6 and IL-8 production. The treatment of HGFs with a CD36 inhibitor also inhibited Pal-induced pro-inflammatory responses. Furthermore, we demonstrated that P. gingivalis LPS and
heat-killed P. gingivalis augmented Pal-induced chemokine secretion in HGFs [33] (Fig. 1). A study has reported that Pal exhibits inflammatory potential accelerating alveolar bone loss in an experimental periodontal disease model in obese mice and affecting the pro-inflammatory osteoclastic response to P. gingivalis infection in vitro [34]. LPS derived from Aggregatibacter actinomycetemcomitans has also been found to augment high-fat-diet-induced CD36 expression in periodontal tissues [35]. In addition to their role in the pathogenesis of periodontitis, P. gingivalis and P. gingivalis LPS could augment high-fat-diet-induced and Pal-induced endothelial injury [36] and steatohepatitis [37]. These results suggest a potential link between plasma FFAs and the pathogenesis of periodontitis. Recent studies have demonstrated that lipid-related molecules may improve the condition of patients with periodontitis. For example, DHA supplementation was reported to improve the periodontal condition of patients with periodontitis [38], and resolvin D1 was found to decrease P. gingivalis-induced chemokine secretion in HGFs [39]. Moreover, resolvin E1, a lipid mediator derived from eicosapentaenoic acid (EPA), can protect against local inflammation and osteoclast-mediated bone destruction in periodontitis [40]. In agreement with these findings, a study found that the ratio of n3 (antiinflammatory) to n6 (pro-inflammatory) polyunsaturated fatty acids, i.e., (DHA þ EPA)/arachidonic acid, was significantly lower in the gingival crevicular fluid of patients with aggressive periodontitis [41].
4. Potential role of Pal in the pathogenesis of cardiovascular diseases The molecular mechanisms of vascular inflammation and atherosclerosis have been extensively studied, and the crucial role of vascular endothelial cell adhesion molecules, such as ICAM-1 and E-selectin, in the interaction between leukocytes and the vascular endothelium has been established. The expression of these adhesion molecules facilitates the binding of leukocytes to the activated endothelium, which is critical for the pathogenesis of cardiovascular diseases [42,43]. The IL-1 signaling pathway is important for inducing the expression and release of adhesion molecules in vascular endothelial cells [44,45]. IL-1β, a prototypic pro-inflammatory cytokine, also plays a crucial role in the pathogenesis of T2D [46] and cardiovascular diseases [47]. Mouse models of atherosclerosis have demonstrated the pro-atherogenic properties of IL-1β associated with the up-regulation of endothelial adhesion molecules, which are responsible for monocyte adhesion and migration [48,49]. IL-1Ra is another member of the IL-1 family that can bind to IL-1 receptors without signal transduction, acting as a naturally occurring antagonist. The production of IL-1β and IL-1Ra in monocytes is differentially regulated [50,51], and their secretion ratio (IL-1β/IL-1Ra; designated as ‘β/Ra') is crucial for vascular inflammation and atherosclerosis [48,49,52]. Moreover, a recent study has demonstrated the essential role of IL-1β signaling in the formation of experimental abdominal aortic aneurysm, which could be attenuated by recombinant IL-1Ra (anakinra) supplementation [53], thus indicating the protective effects of IL-1Ra supplementation against vascular inflammation and atherosclerosis. Although Pal has been reported to induce IL-1β secretion in human monocytes [5], little is known about the effects of Pal on IL-1Ra secretion in human monocytes or the effects of Pal-induced secretion on adhesion molecule expression in vascular endothelial cells. Therefore, we have examined the indirect effects of Pal on the expression and release of ICAM-1 and E-selectin in vascular endothelial cells. SFAs but not UFAs were found to increase IL-1β secretion and decrease L-1Ra secretion, resulting in an increase in the β/Ra secretion ratio. UFAs dose-dependently inhibited the increase in IL-1β secretion and the decrease in IL-1Ra secretion
Please cite this article as: Shikama Y. Free fatty acids may be involved in the pathogenesis of oral-related and cardiovascular diseases. J Oral Biosci (2018), https://doi.org/10.1016/j.job.2018.04.001i
Y. Shikama / Journal of Oral Biosciences ∎ (∎∎∎∎) ∎∎∎–∎∎∎
Pal
3
Pal
TLRs
TLRs CD36
CD36
HGF
HGF IL-8 CXCL1
IL-6 IL-8 CXCL1
Monocytes/Neutrophils Monocytes/Neutrophils Fig. 1. Potential mechanism of the involvement of Pal in the pathogenesis of periodontitis. Left panel: Pal induces IL-6, IL-8, and CXCL1 production in HGFs. Right panel: Pal augments P. gingivalis-induced IL-8 and CXCL1 production in HGFs, resulting in the accumulation of monocytes and neutrophils in periodontal tissues.
A) Normal Vascular endothelial cells
IL-1
Monocytes
IL-1Ra
IL-1R1
Promotes plaque formation
B) SFA-rich condition in plasma
Pal
IL-1Ra Rolling
IL-1
Firm adhesion
/Ra IL-1R1 E-selectin
ICAM-1
Facilitates trans-endothelial migration of leukocytes
Fig. 2. Potential mechanism of the involvement of Pal in the pathogenesis of cardiovascular diseases. A) Under healthy conditions, the expression of adhesion molecules (ICAM-1 and E-selectin) is low in vascular endothelial cells because β/Ra is well balanced in the plasma. B) Under SFA-rich conditions, Pal increases IL-1β production and decreases IL-1Ra production in monocytes, resulting in an increase in β/Ra in the plasma. This induces the expression of adhesion molecules mediated by IL-1 receptor 1 (IL1R1) signaling in vascular endothelial cells, promoting plaque formation and facilitating the trans-endothelial migration of leukocytes.
induced by Pal. Moreover, in human aortic and vein endothelial cells, the expression and release of ICAM-1 and E-selectin were induced by treatment with conditioned medium collected from Pal-stimulated human monocytes but not by treatment with Pal only. The up-regulated expression and release of adhesion molecules by the conditioned medium were mostly abolished by recombinant human IL-1Ra supplementation. These results suggest that the Pal-induced increase in the ratio of β/Ra secretion in monocytes can up-regulate endothelial adhesion molecules, which may enhance leukocyte adhesion to the endothelium [54] (Fig. 2). In rodent models, IL-1Ra-deficient mice were reported to exhibit impaired lipid metabolism following high-fat-diet-induced
inflammation [55], and IL-1Ra administration was found to reduce hyperglycemia and tissue inflammation in T2D GK rats [56]. Moreover, preclinical and clinical trial results have indicated that IL-1β blockage may be beneficial for patients who have or are at risk of cardiovascular diseases [57]. The findings partly demonstrate the clinical significance of IL-1Ra treatment in cardiovascular diseases.
5. Conclusion Our study has revealed the importance of FFAs in the pathogenesis of oral-related and cardiovascular diseases. According to
Please cite this article as: Shikama Y. Free fatty acids may be involved in the pathogenesis of oral-related and cardiovascular diseases. J Oral Biosci (2018), https://doi.org/10.1016/j.job.2018.04.001i
Y. Shikama / Journal of Oral Biosciences ∎ (∎∎∎∎) ∎∎∎–∎∎∎
4
our current results and those of previous studies, supplementation with polyunsaturated fatty acids or these derivatives may be beneficial for the treatment of primary SS, periodontitis, and cardiovascular diseases. Nevertheless, further research on the association between lipid-related molecules and the pathogenesis of these diseases is needed to develop novel therapeutic strategies.
Acknowledgments The author would like to thank Yasusei Kudo, Naozumi Ishimaru (Tokushima University, Japan), and Makoto Funaki (Tokushima University Hospital, Japan) for the experimental studies discussed in this review.
[13] [14]
[15]
[16] [17]
[18] [19] [20]
Ethical approval
[21]
This review did not require ethical approval. [22]
Conflict of interest The authors declare no conflict of interest.
Funding This study was supported in part by a Grant-in-Aid for Research Activity Start-up from the Ministry of Education, Culture, Sports, Science and Technology (16H07017 to Y.S.) and Research Funding for Longevity Sciences (29-19 to Y.S.) from the National Center for Geriatrics and Gerontology (NCGG), Japan.
[23]
[24]
[25]
[26] [27]
[28]
References [29] [1] Kopelman P. Health risks associated with overweight and obesity. Obes Rev 2007;8:13–7. [2] Boden G. Interaction between free fatty acids and glucose metabolism. Curr Opin Clin Nutr Metab Care 2002;5:545–9. [3] Cnop M. Fatty acids and glucolipotoxicity in the pathogenesis of type 2 diabetes. Biochem Trans 2008;36:348–52. [4] Maloney E, Sweet IR, Hockenbery DM, Pham M, Rizzo NO, Tateya S, Handa P, Schwartz MW, Kim F. Activation of NF-κB by palmitate in endothelial cells: a key role for NADPH oxidase-derived superoxide in response to TLR4 activation. ArteriosclerThrombVasc Biol 2009;29:1370–5. [5] Snodgrass RG, Huang S, Choi IW, Rutledge JC, Hwang DH. Inflammasomemediated secretion of IL-1β in human monocytes through TLR2 activation; modulation by dietary fatty acids. J Immunol 2013;191:4337–47. [6] Chavez JA, Summers SA. Characterizing the effects of saturated fatty acids on insulin signaling and ceramide and diacylglycerol accumulation in 3T3-L1 adipocytes and C2C12 myotubes. Arch Biochem 2003;419:101–9. [7] Coll T, Eyre E, Rodriguez-Calvo R, Palomer X, Sanchez RM, Merlos M, Laguna JC, Vazquez-Carrera M. Oleate reverses palmitate-induced insulin resistance and inflammation in skeletal muscle cells. J Biol Chem 2008;283:11107–16. [8] Sinha S, Perdomo G, Brown NF, O'Doherty RM. Fatty acid-induced insulin resistance in L6 myotubes is prevented by inhibition of activation and nuclear localization of nuclear factor kappa B. J Biol Chem 2004;279:41294–301. [9] Yuzefovych L, Wilson G, Rachek L. Different effects of oleate vs. palmitate on mitochondrial function, apoptosis, and insulin signaling in L6 skeletal muscle cells: role of oxidative stress. Am J Physiol Endocrinol Metab 2010;299:E1096–105. [10] Peng G, Li L, Liu Y, Pu J, Zhang S, Yu J, Zhao J, Liu P. Oleate blocks palmitateinduced abnormal lipid distribution, endoplasmic reticulum expansion and stress, and insulin resistance in skeletal muscle. Endocrinology 2011;152:2206–18. [11] Turpin SM, Lancaster GI, Darby I, Febbraio MA, Watt MJ. Apoptosis in skeletal muscle myotubes is induced by ceramides and is positively related to insulin resistance. Am J Physiol Endocrinol Metab 2006;291:E1341–50. [12] Bunn RC, Cockrell GE, Ou Y, Thrailkill KM, Lumpkin Jr CK, Fowlkes JL. Palmitate
[30] [31]
[32]
[33] [34]
[35]
[36]
[37]
[38]
[39]
and insulin synergistically induce IL-6 expression in human monocytes. Cardiovasc Diabetol 2010;9:73. Riserus U, Willett WC, Hu FB. Dietary fats and prevention of type 2 diabetes. Prog Lipid Res 2009;48:44–51. Campbell SE, Tandon NN, Woldegiorgis G, Luiken JJ, Glatz JF, Bonen A. A novel function for fatty acid translocase (FAT)/CD36: involvement in long chain fatty acid transfer into the mitochondria. J Biol Chem 2004;279:36235–41. Stewart CR, Stuart LM, Wilkinson K, van Gils JM, Deng J, Halle A, Rayner KJ, Boyer L, Zhong R, Frazier WA, Lacy-Hulbert A, El Khoury J, Golenbock DT, Moore KJ. CD36 ligands promote sterile inflammation through assembly of a Toll-like receptor 4 and 6 heterodimer. Nat Immunol 2010;11:155–61. Kusminski CM, Shetty S, Orci L, Unger RH, Scherer PE. Diabetes and apoptosis: lipotoxicity. Apoptosis 2009;14:1484–95. Nelson RG, Shlossman M, Budding LM, Pettitt DJ, Saad MF, Genco RJ, Knowler WC. Periodontal disease and NIDDM in Pima Indians. Diabetes Care 1990;13:836–40. Saito T, Shimazaki Y, Sakamoto M. Obesity and periodontitis. N Engl J Med 1998;339:482–3. Tervonen T, Karjalainen K, Knuuttila M, Huumonen S. Alveolar bone loss in type 1 diabetic subjects. J Clin Periodontol 2000;27:567–71. Kang JH, Lin HC. Comorbidities in patients with primary Sjögren's syndrome: a registry-based case-control study. J Rheumatol 2010;37:1188–94. Ramos-Casals M, Brito-Zeron P, Siso A, Vargas A, Ros E, Bove A, Belenguer R, Plaza J, Benavent J, Font J. High prevalence of serum metabolic alterations in primary Sjögren's syndrome: influence on clinical and immunological expression. J Rheumatol 2007;34:754–61. Sekiguchi M, Iwasaki T, Kitano M, Kuno H, Hashimoto N, Kawahito Y, Azuma M, Hla T, Sano H. Role of sphingosine 1-phosphate in the pathogenesis of Sjögren's syndrome. J Immunol 2008;180:1921–8. Chan EK, Hamel JC, Buyon JP, Tan EM. Molecular definition and sequence motifs of the 52-kD component of human SS-A/Ro autoantigen. J Clin Invest 1991;87:68–76. Haneji N, Nakamura T, Takio K, Yanagi K, Higashiyama H, Saito I, Noji S, Sugino H, Hayashi Y. Identification of α-fodrin as a candidate autoantigen in primary Sjögren's syndrome. Science 1997;276:604–7. Shikama Y, Ishimaru N, Kudo Y, Bando Y, Aki N, Hayashi Y, Funaki M. Effects of free fatty acids on human salivary gland epithelial cells. J Dent Res 2013;92:540–6. Leigh NJ, Nelson JW, Mellas RE, Aguirre A, Baker OJ. Expression of resolvin D1 biosynthetic pathways in salivary epithelium. J Dent Res 2014;93:300–5. Azuma M, Aota K, Tamatani T, Motegi K, Yamashita T, Harada K, Hayashi Y, Sato M. Suppression of tumor necrosis factor α-induced matrix metalloproteinase 9 production by the introduction of a super-repressor form of inhibitor of nuclear factor κBα complementary DNA into immortalized human salivary gland acinar cells: prevention of the destruction of the acinar structure in Sjögren's syndrome salivary glands. Arthritis Rheum 2000;43:1756–67. Nelson JW, Leigh NJ, Mellas RE, McCall AD, Aguirre A, Baker OJ. ALX/FPR2 receptor for RvD1 is expressed and functional in salivary glands. Am J Physiol Cell Physiol 2014;306:C178–85. Odusanwo O, Chinthamani S, McCall A, Duffey ME, Baker OJ. Resolvin D1 prevents TNF-α-mediated disruption of salivary epithelial formation. Am J Physiol Cell Physiol 2012;302:C1331–45. Darveau RP. Periodontitis: a polymicrobial disruption of host homeostasis. Nat Rev Microbiol 2010;8:481–90. Almasri A, Wisithphrom K, Windsor LJ, Olson B. Nicotine and lipopolysaccharide affect cytokine expression from gingival fibroblasts. J Periodontol 2007;78:533–41. Kusumoto Y, Hirano H, Saitoh K, Yamada S, Takedachi M, Nozaki T, Ozawa Y, Nakahira Y, Saho T, Ogo H, Shimabukuro Y, Okada H, Murakami S. Human gingival epithelial cells produce chemotactic factors interleukin-8 and monocyte chemoattractant protein-1 after stimulation with Porphyromonasgingivalis via toll-like receptor 2. J Periodontol 2004;75:370–9. Shikama Y, Kudo Y, Ishimaru N, Funaki M. Possible involvement of palmitate in pathogenesis of periodontitis. J Cell Physiol 2015;230:2981–9. Muluke M, Gold T, Kiefhaber K, Al-Sahli A, Celenti R, Jiang H, Cremers S, Van Dyke T, Schulze-Spate U. Diet-induced obesity and its differential impact on periodontal bone loss. J Dent Res 2016;95:223–9. Lu Z, Li Y, Brinson CW, Kirkwood KL, Lopes-Virella MF, Huang Y. CD36 is upregulated in mice with periodontitis and metabolic syndrome and involved in macrophage gene upregulation by palmitate. Oral Dis 2017;23:210–8. Ao M, Miyauchi M, Inubushi T, Kitagawa M, Furusho H, Ando T, Ayuningtyas NF, Nagasaki A, Ishihara K, Tahara H, Kozai K, Takata T. Infection with Porphyromonasgingivalis exacerbates endothelial injury in obese mice. PLoS One 2014;9:e110519. Furusho H, Miyauchi M, Hyogo H, Inubushi T, Ao M, Ouhara K, Hisatune J, Kurihara H, Sugai M, Hayes CN, Nakahara T, Aikata H, Takahashi S, Chayama K, Takata T. Dental infection of Porphyromonasgingivalis exacerbates high fat diet-induced steatohepatitis in mice. J Gastroenterol 2013;48:1259–70. Naqvi AZ, Hasturk H, Mu L, Phillips RS, Davis RB, Halem S, Campos H, Goodson JM, Van Dyke TE, Mukamal KJ. Docosahexaenoic acid and periodontitis in adults: a randomized controlled trial. J Dent Res 2014;93:767–73. Khaled M, Shibani NA, Labban N, Batarseh G, Song F, Ruby J, Windsor LJ. Effects of resolvin D1 on cell survival and cytokine expression of human gingival
Please cite this article as: Shikama Y. Free fatty acids may be involved in the pathogenesis of oral-related and cardiovascular diseases. J Oral Biosci (2018), https://doi.org/10.1016/j.job.2018.04.001i
Y. Shikama / Journal of Oral Biosciences ∎ (∎∎∎∎) ∎∎∎–∎∎∎ fibroblasts. J Periodontol 2013;84:1838–46. [40] Hasturk H, Kantarci A, Ohira T, Arita M, Ebrahimi N, Chiang N, Petasis NA, Levy BD, Serhan CN, Van Dyke TE. RvE1 protects from local inflammation and osteoclast- mediated bone destruction in periodontitis. FASEB J 2006;20:401–3. [41] Elabdeen HR, Mustafa M, Szklenar M, Ruhl R, Ali R, Bolstad AI. Ratio of proresolving and pro-inflammatory lipid mediator precursors as potential markers for aggressive periodontitis. PLoS One 2013;8:e70838. [42] Springer TA. Traffic signals for lymphocyte recirculation and leukocyte emigration: the multistep paradigm. Cell 1994;76:301–14. [43] Woollard KJ, Geissmann F. Monocytes in atherosclerosis: subsets and functions. Nat Rev Cardiol 2010;7:77–86. [44] Haraldsen G, Kvale D, Lien B, Farstad IN, Brandtzaeg P. Cytokine-regulated expression of E-selectin, intercellular adhesion molecule-1 (ICAM-1), and vascular cell adhesion molecule-1 (VCAM-1) in human microvascular endothelial cells. J Immunol 1996;156:2558–65. [45] Szekanecz Z, Shah MR, Pearce WH, Koch AE. Intercellular adhesion molecule-1 (ICAM-1) expression and soluble ICAM-1 (sICAM-1) production by cytokineactivated human aortic endothelial cells: a possible role for ICAM-1 and sICAM-1 in atherosclerotic aortic aneurysms. Clin Exp Immunol 1994;98:337–43. [46] Maedler K, Sergeev P, Ris F, Oberholzer J, Joller-Jemelka HI, Spinas GA, Kaiser N, Halban PA, Donath MY. Glucose-induced β cell production of IL-1β contributes to glucotoxicity in human pancreatic islets. J Clin Invest 2002;110:851–60. [47] von der Thusen JH, Kuiper J, van Berkel TJ, Biessen EA. Interleukins in atherosclerosis: molecular pathways and therapeutic potential. Pharmacol Rev 2003;55:133–66. [48] Kirii H, Niwa T, Yamada Y, Wada H, Saito K, Iwakura Y, Asano M, Moriwaki H, Seishima M. Lack of interleukin-1β decreases the severity of atherosclerosis in ApoE-deficient mice. ArteriosclerThromb Vasc Biol 2003;23:656–60.
5
[49] Takahashi M, Ikeda U, Masuyama J, Kitagawa S, Kasahara T, Shimpo M, Kano S, Shimada K. Monocyte-endothelial cell interaction induces expression of adhesion molecules on human umbilical cord endothelial cells. Cardiovasc Res 1996;32:422–9. [50] Arend WP, Smith Jr MF, Janson RW, Joslin FG. IL-1 receptor antagonist and IL-1 beta production in human monocytes are regulated differently. J Immunol 1991;147:1530–6. [51] Poutsiaka DD, Clark BD, Vannier E, Dinarello CA. Production of interleukin-1 receptor antagonist and interleukin-1 beta by peripheral blood mononuclear cells is differentially regulated. Blood 1991;78:1275–81. [52] Arend WP. The balance between IL-1 and IL-1Ra in disease. Cytokine Growth Factor Rev 2002;13:323–40. [53] Johnston WF, Salmon M, Su G, Lu G, Stone ML, Zhao Y, Owens GK, Upchurch Jr GR, Ailawadi G. Genetic and pharmacologic disruption of interleukin-1β signaling inhibits experimental aortic aneurysm formation. ArteriosclerThromb Vasc Biol 2013;33:294–304. [54] Shikama Y, Aki N, Hata A, Nishimura M, Oyadomari S, Funaki M. Palmitatestimulated monocytes induce adhesion molecule expression in endothelial cells via IL-1 signaling pathway. J Cell Physiol 2015;230:732–42. [55] Isoda K, Sawada S, Ayaori M, Matsuki T, Horai R, Kagata Y, Miyazaki K, Kusuhara M, Okazaki M, Matsubara O, Iwakura Y, Ohsuzu F. Deficiency of interleukin-1 receptor antagonist deteriorates fatty liver and cholesterol metabolism in hypercholesterolemic mice. J Biol Chem 2005;280: 7002–7009. [56] Ehses JA, Lacraz G, Giroix MH, Schmidlin F, Coulaud J, Kassis N, Irminger JC, Kergoat M, Portha B, Homo-Delarche F, Donath MY. IL-1 antagonism reduces hyperglycemia and tissue inflammation in the type 2 diabetic GK rat. Proc Natl Acad Sci USA 2009;106:13998–4003. [57] Van Tassell BW, Toldo S, Mezzaroma E, Abbate A. Targeting interleukin-1 in heart disease. Circulation 2013;128:1910–23.
Please cite this article as: Shikama Y. Free fatty acids may be involved in the pathogenesis of oral-related and cardiovascular diseases. J Oral Biosci (2018), https://doi.org/10.1016/j.job.2018.04.001i