Peroksizom Proliferatör ile Etkinleştirilen Reseptörlerin İnsülin Direnci ve Septik Şok Patojenezindeki Rolü

Peroksizom proliferatör ile etkinleştirilen reseptörler ligant ile etkin¬leştirilen transkripsiyon faktörleridir ve sınıf II nükleer reseptör ailesine aittirler. Günümüze dek peroksizom proliferatör ile etkinleştirilen resep¬tör (peroxisome proliferator-activated receptor; PPAR) α, PPARβ ve PPARγ olmak üzere 3 alt tür tanımlanmıştır. PPARα başlıca lipit metabolizması ve enflamatuvar sürecin düzenlenmesinde rol oynamaktadır. PPARα ve PPARγ üzerine yapılan çok sayıdaki çalışmaya karşın, PPARβ’nın işlevsel kimliği henüz netlik kazanmamıştır; çünkü neredeyse tüm dokularda eksprese edilmektedir. PPARγ ise glukoz homeostazı ve adipojenezin düzenlenmesinde anahtar rol oynar. İnsülin direnci kandaki normal ya da yüksek insülin düzeyine rağmen, zayıf biyolojik yanıt oluşmasıdır. İnsülin direncinde başta kas, yağ ve karaciğer olmak üzere tüm dokularda insü¬line gerekli ve yeterli yanıt oluşmamaktadır. PPARα lipit metabolizması üzerine etkili genleri düzenleyerek, PPARγ ise çeşitli mekanizmalar ile glukoz homeostazını sağlayarak insülin direnci ortaya çıkmasını engeller. Sepsis, bilinen veya olası bir enfeksiyona karşı verilen sistemik enflama-tuvar yanıt durumu, septik şok ise intravenöz sıvı uygulamasına yanıtsız hipotansiyonun eşlik ettiği şiddetli sepsistir. PPAR agonistleri ile yapılan klinik öncesi çalışmalarda sepsis ve septik şok patojenezinde rol oynayan nükleer faktör κB ve etkinleştirici protein-1 gibi transkripsiyon faktörle-rinin etkinleşmesi inhibe edilerek proenflamatuvar gen ekspresyonunun engellendiği görülmüştür. Bu derlemede, insülin direnci ve septik şok patojenezinde PPAR’ların rolüne değinilerek, PPAR agonistlerinin olası terapötik yararları üzerinde durulmuştur.

Anahtar Kelimeler:

PPAR, septik şok, insülin direnci, enflamasyon

The Role of Peroxisome Proliferator-Activated Receptors in the Pathogenesis of Insulin Resistance and Septic Shock

Peroxisome proliferator-activated receptors are ligand-activated transcription factors and they belong to class II nuclear receptor family. To date, three subspecies have been identified: peroxisome proliferator-activated receptor (PPAR) α, PPARβ and PPARγ. PPARα is mainly involved in the regulation of lipid metabolism and inflammatory processes. Since PPARβ is expressed in almost all tissues, the functional identity of it is not yet clear. PPARγ plays a key role in glucose homeostasis and the regulation of adipogenesis. Insulin resistance is attenuated biological response despite circulating normal or high levels of insulin in blood. In insulin resistance, the response caused by insulin isn’t sufficient or adequate at all tissues particularly in muscle, fat and liver. Development of insulin resistance is prevented by PPARα through regulation of genes affecting lipid metabolism and by PPARγ through provision of glucose homeostasis by different mechanisms. Sepsis is a systemic inflammatory response against a manifest or a potential infection; and septic shock is the severe form of sepsis that is accompanied by hypotension unresponsive to intravenous fluid administration. In preclinical studies proinflammatory gene expression was prevented by the inhibition of activation of transcription factors such as nuclear factor κB and activator protein-1 which are involved in the pathogenesis of sepsis and septic shock by PPAR agonists. This review focuses on the role of PPARs in the pathogenesis of insulin resistance and septic shock and discusses the potential therapeutic benefits of PPAR agonists.

Keywords:

PPAR, insulin resistance, septic shock, inflammation,

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1. Issemann I, Green S. Activation of a member of the steroid hormone receptor superfamily by peroxisome proliferators. Nature. 1990; 347: 645-650.
2. Dreyer C, Krey G, Keller H, Givel F, Helftenbein G, Wahli W. Control of the peroxisomal β- oxidation pathway by a novel family of nuclear hormone receptors. Cell. 1992; 68: 879-887.
3. Zhu Y , Alvares K, Huang Q, Rao MS, Reddy JK. Cloning of a new member of the peroxisome proliferator-activated receptor gene family from mouse liver. J Biol Chem. 1993; 268: 26817-26820.
4. Tontonoz P, Hu E, Graves RA, Budavari AI, Spiegelman BM. mPPARγ 2: tissue-specific regulator of an adipocyte enhancer. Genes Dev. 1994; 8: 1224-1234.
5. Kliewer SA, Forman BA, Blumberg B, Ong ES, Borgmeyer U, Mangelsdorf DJ, Umesono K, Evans RM. Differential expression and activation of a family of murine peroxisome proliferator-activated receptors. Proc Natl Acad Sci US. 1994; 91: 7355-7359.
6. LeRoith D, Taylor SI, Olefsky JM. Peroxisome proliferator-activated receptor modulators. Diabetes Mellitus: A Fundamental and Clinical Text. 3rd ed. Philadelphia: Lippincott Williams & Wilkins; 2004. p. 1140.
7. Grygiel-Górniak B. Peroxisome proliferator-activated receptors and their ligands: nutritional and clinical implications-a review. Nutr J. 2014; 13: 17.
8. Wright MB, Bortolini M, Tadayyon M, Bopst M. Mini review: challenges and opportunities in development of PPAR agonists. Mol Endocrinol. 2014; 28: 1756-1768.
9. Glass CK, Ogawa S. Combinatorial roles of nuclear receptors in inflammation and immunity. Nat Rev Immunol. 2006; 6: 44-55.
10. Aydogan HY, Kurt O, Kurnaz O, Teker BA, Kucukhuseyin O. Peroxisome proliferator-activated receptor (PPAR) isoforms in coronary heart disease Turk J Biochem. 2013; 38: 372-384.
11. Kiec-Wilk B, Dembinska-Kiec A, Olszanecka A, Bodzioch M, Kawecka- Jaszcz K. The selected pathophysiological aspects of PPARs activation. J Physiol Pharmacol. 2005; 56: 149-162.
12. Kota BP, Huang TH, Roufogalis BD. An overview on biological mechanisms of PPARs. Pharmacol Res. 2005; 51: 85-94.
13. Schoonjans K, Peinado-Onsurbe J, Heyman R, Briggs M, Caayet D, Deeb S, Staels B, Auwerx J. PPAR alpha and PPAR gamma activators direct a distinct tissue-specific transcriptional response via a PPRE in the lipoprotein lipase gene. EMBO J. 1996; 15: 5336-5348.
14. Libby P, Plutzky J. Inflammation in diabetes: Role of peroxisome proliferator-activated receptor-α and receptor-γ agonists. Am J Cardiol. 2007; 19: 27B-40B.
15. Chinetti G, Griglio S, Antonucci M, Torra IP, Delerive P, Majd Z, Fruchart JC, Chapman J, Najib J, Staels B. Activation of proliferator-activated receptors α and γ induces apoptosis of human monocytederived macrophages. J Biol Chem. 1998; 273: 25573-25580.
16. Staels B, Koenig W, Habib A, Merval R, Lebret M, Torra IP, Delerive P, Fadel A, Chinetti G, Fruchart JC, Najib J, Maclouf J, Tedgui A. Activation of human aortic smooth-muscle cells is inhibited by PPARα but not by PPARγ activators. Nature. 1998; 393: 790-793.
17. Delerive P, Martin-Nizard F, Chinetti G, Trottein F, Fruchart JC, Najib J, Duriez P, Staels B. Peroxisome proliferator-activated receptor activators inhibit thrombin-induced endothelin-1 production in human vascular endothelial cells by inhibiting the activator protein-1 signaling pathway. Circ Res. 1999; 85: 394-402.
18. Marx N, Sukhova GK, Collins T, Libby P, Plutzky J. PPARα activators inhibit cytokine-induced vascular cell adhesion molecule-1 expression in human endothelial cells. Circulation. 1999; 99: 3125- 3131.
19. Tugwood JD, Issemann I, Anderson RG, Bundell KR, McPheat WL, Green S. The mouse peroxysome proliferator-activated receptor recognizes a response element in the 50 flanking sequence of the rat acyl coA oxidase gene. EMBO J. 1992; 11: 433-439.
20. Plutzky J. Macrovascular effects and safety issues of therapies for type 2 diabetes. Am J Cardiol. 2011; 108: 25B-32B.
21. Plutzky J. The PPAR-RXR transcriptional complex in the vasculature: energy in the balance. Circ Res. 2011; 108: 1002-1016. 22. Oyekan A. PPARs and their effects on the cardiovascular system. Clin Exp Hypertens. 2011; 33: 287-293.
23. Schultze AE, Alborn WE, Newton RK, Konrad RJ. Administration of a PPARalpha agonist increases serum apolipoprotein A-V levels and the apolipoprotein A-V/apolipoprotein C-III ratio. J Lipid Res. 2005; 46: 1591-1595.
24. Schoonjans K, Staels B, Auwerx J. The peroxisome proliferator activated receptors (PPARs) and their effects on lipid metabolism and adipocyte differentiation. Biochim Biophys Acta. 1996; 1302: 93-109.
25. Braissant O, Foufelle F, Scotto C, Dauca M, Wahli W. Differential expression of peroxisome proliferator-activated receptors (PPARs): tissue distribution of PPAR-alpha, -β, and -gamma in the adult rat. Endocrinology. 1996; 137: 354-366.
26. Rocchi S, Auwerx J. Peroxisome proliferator-activated receptor-gamma: a versatile metabolic regulator. Ann Med. 1999; 31: 342-351.
27. Cefalu WT. Insulin resistance: cellular and clinical concepts. Exp Biol Med (Mywood). 2001; 226: 13-26.
28. Kayaalp SO. Endokrin sistem farmakolojisi. Akılcıl Tedavi Yönünden Tıbbi Farmakoloji 1-2. 13. Baskı, Ankara: Pelikan Kitabevi; 2012. s. 1280. 29. DeFronzo RA. Pathogenesis of type 2 diabetes: metabolic and molecular implications for identifying diabetes genes. Diabetes Rev. 1998; 5: 177-269.
30. Işıldak M, Güven GS, Gürlek A. Metabolik sendrom ve insülin direnci. Hacettepe Tıp Dergisi. 2004; 35: 96-99.
31. Savage DV, Petersen KF, Shulman GI. Mechanisms of insulin resistance in humans and possible links with inflammation. Hypertension. 2005; 45: 828-833.
32. Aygün G. Sepsis ve septik şok. Akılcı Antibiyotik Kullanımı ve Erişkinde Toplumdan Edinilmiş Enfeksiyonlar Sempozyum Dizisi. No: 31. 2002. 131-140.
33. Sutton SS. Sepsis and septic shock. In: Chisholm-Burns MA, Wells BG, Schwinghammer TL, Malone PM, Kolesar JM, Rotschafer JC, Dipiro JT, eds. Pharmacotherapy: Principles & Practice. ABD: The McGraw-Hill Companies Inc; 2008. p. 1185-1197.
34. Martin JB, Wheeler AP. Approach to the patient with sepsis. Clin Chest Med. 2009; 30: 1-16.
35. Morrell MR, Micek ST, Kollef MH. The management of severe sepsis and septic shock. Infect Dis Clin North Am. 2009; 23: 485-501.
36. Silva E, Passos Rda H, Ferri MB, de Figueiredo LF. Sepsis: from bench to bedside. Clinics. 2008; 63: 109-120.
37. Brown J, Wang H, Hajishengallis GN, Martin M. TLR-signaling networks: An integration of adaptor molecules, kinases and cross-talk. J Dent Res. 2011; 90: 417-427. 38. Frick MH, Elo O, Haapa K, Heinonen OP, Heinsalmi P, Helo P, Huttunen JK, Kaitaniemi P, Koskinen P, Manninen V, Mäenpää H, Mälkönen M, Mänttäri M, Norola S, Pasternack A, Pikkarainen J, Romo M, Sjöblom T, Nikkilä EA. Helsinki Heart Study: primary-prevention trial with gemfibrozil in middle-aged men with dyslipidemia. Safety of treatment, changes in risk factors, and incidence of coronary heart disease. N Engl J Med. 1987; 317: 1237-1245.
39. Frick MH, Syvanne M, Nieminen MS, Kauma H, Majahalme S, Virtanen V, Kesaniemi YA, Pasternack A, Taskinen MR, for the Lopid Coronary Angiography Trial (LOCAT) Study Group. Prevention of the angiographic progression of coronary and vein-graft atherosclerosis by gemfibrozil after coronary bypass surgery in men with low levels of HDL cholesterol. Circulation. 1997; 96: 2137-2143.
40. Rubins HB, Robins SJ, Collins D, Fye CL, Anderson JW, Elam MB, Faas FH, Linares E, Schaefer EJ, Schectman G, Wilt TJ, Wittes J. Gemfibrozil for the secondary prevention of coronary heart disease in men with low levels of high-density lipoprotein cholesterol. N Engl J Med. 1999; 341: 410-418.
41. BIP Study Group. Secondary prevention by raising HDL cholesterol and reducing triglycerides in patients with coronary artery disease: the Bezafibrate Infarction Prevention (BIP) study. Circulation. 2000; 102: 21-27.
42. Diabetes Atherosclerosis Intervention Study Investigators. Effect of fenofibrate on progression of coronary-artery disease in type 2 diabetes: the Diabetes Atherosclerosis Intervention Study, a randomised study. Lancet. 2001; 357: 905-910.
43. Heller F, Harvengt C. Effects of clofibrate, bezafibrate, fenofibrate and probucol on plasma lipolytic enzymes in normolipaemic subjects. Eur J Clin Pharmacol. 1983; 25: 57-63.
44. Malmendier CL, Delcroix C. Effects of fenofibrate on high and low density lipoprotein metabolism in heterozygous familial hypercholesterolemia. Atherosclerosis. 1985; 55: 161-169.
45. Staels B, Auwerx J. Regulation of apo A-I gene expression by fibrates. Atherosclerosis. 1998; 137: 19-23.
46. Semple RK, Chatterjee VKK, O’Rahilly S. PPARγ and human metabolic disease. J Clin Invest. 2006; 116: 581-589.
47. Rangwala SM, Lazar MA. Peroxisome proliferator-activated receptor γ in diabetes and metabolism. Trends Pharmacol Sci. 2004; 25: 331-336.
48. Plutzky J. PPARs and Cardiovascular Disease Risk Reduction in Patients with Type 2 Diabetes. [updated 2012 June 29; cited 2013 June 29]. Available from: http://www.medscape.org/viewarticle/765568.
49. Tunctan B, Korkmaz B, Sari AN, Kacan M, Unsal D, Serin MS, Buharalioglu CK, Sahan-Firat S, Schunck WH, Falck JR, Malik KU. A novel treatment strategy for sepsis and septic shock based on the interactions between prostanoids, nitric oxide, and 20-hydroxyeicosatetraenoic acid. Antiinflamm Antiallergy Agents Med Chem. 2012; 11: 121-150.
50. Sutton SS. Sepsis and septic shock. In: Chisholm-Burns MA, Wells BG, Schwinghammer TL, Malone PM, Kolesar JM, Rotschafer JC, Dipiro JT, eds. Pharmacotherapy: Principles & Practice, ABD: The McGraw-Hill Companies Inc, 2008. p. 1185-1197. 51. Martin JB, Wheeler AP. Approach to the patient with sepsis. Clin Chest Med. 2009; 30: 1-16.
52. Morrell MR, Micek ST, Kollef MH. The management of severe sepsis and septic shock. Infect Dis Clin North Am. 2009; 23: 485-501.
53. Brown J, Wang H, Hajishengallis GN, Martin M. TLR-signaling networks: An integration of adaptor molecules, kinases and cross-talk. J Dent Res. 2011; 90: 417-427.
54. Gao H, Evans TW, Finney S. Bench-to-bedside review: sepsis, severe sepsis and septic shock - does the nature of the infecting organism matter? J Crit Care. 2008; 12: 213.
55. Gustot, T. Multiple organ failure in sepsis: prognosis and role of systemic inflammatory response. Curr Opin Crit Care. 2011; 17: 153- 159. 56. Kellum JA, Kong L, Fink MP, Weissfeld LA, Yealy DM, Pinsky MR, Fine J, Krichevsky A, Delude RL, Angus DC, for the GenIMS Investigators. Understanding the inflammatory cytokine response in pneumonia and sepsis: results of the genetic and inflammatory markers of sepsis (GenIMS) study. Arch Intern Med. 2007; 167: 1655-1663.
57. Latto C. An overview of sepsis. Dimens Crit Care Nurs. 2008; 2: 195- 200.
58. Levy B, Collin S, Sennoun N, Ducrocq N, Kimmoun A, Asfar P, Perez P, Meziani F. Vascular hyporesponsiveness to vasopressors in septic shock: from bench to bedside. Intensive Care Med. 2010; 36: 2019- 2029.
59. Lu YC, Yeh WC, Ohashi PS. LPS/TLR4 signal transduction pathway. Cytokine. 2008; 42: 145-151.
60. Martins PS, Brunialti MK, da Luz Fernandes M, Martos LS, Gomes NE, Rigato O, Salomao R. Bacterial recognition and induced cell activation in sepsis. Endocr Metab Immune Disord Drug Targets. 2006; 6: 1831- 1891.
61. Nduka OO, Parrillo JE. The pathophysiology of septic shock. Crit Care Nurs Clin North Am. 2011; 23: 41-66.
62. Opal SM. Endotoxins and other sepsis triggers. Contrib Nephrol. 2010; 167: 14-24. 63. Rudiger A, Stotz M, Singer M. Cellular processes in sepsis. Swiss Med Wkly. 2008; 138: 629-634.
64. Cavaillon JM, Adib-Conquy M, Fitting C, Adrie C, Payen, D. Cytokine cascade in sepsis. J Infect Dis. 2003; 35: 535-544. 65. Appelmelk BJ, Lynn WA. The cause of sepsis: bacterial cell components that trigger the cytokine cascade. In: Dhainaut JF, Thijs LG, Park G, eds. Septic shock, 1st ed. Chinese: W.B Saunders Co; 2000. p. 21-26.
66. Draing C, Sigel S, Deininger S, Traub S, Munke R, Mayer C, Hareng L, Hartung T, von Aulock S, Hermann C. Cytokine induction by Gram-positive bacteria. Immunobiology. 2008; 213: 285-296.
67. Inagawa H, Kohchi C, Soma G. Oral administration of lipopolysaccharides for the prevention of various diseases: benefit and usefulness. Anticancer Res. 2011; 31: 2431-2436.
68. Majcherczyk PA, Langen H, Heumann D, Fountoulakis M, Glauser MP, Moreillon P. Digestion of streptococcus pneumoniae cell walls with its major peptidoglycan hydrolase releases branched stem peptides carrying proinflammatory activity. Biol Chem. 1999; 274: 12537-12543.
69. Rietschel ET, Kirikae T, Schade FU, Mamat U, Schmidt G, Loppnow H, Ulmer AJ, Zahringer U, Seydel U, Di Padova F, Schreier M, Brade H. Bacterial endotoxin: molecular relationships of structure to activity and function. FASEB J. 1994; 8: 217-225.
70. Seydel U, Oikawa M, Fukase K, Kusumoto S, Brandenburg K. Intrinsic conformation of lipid A is responsible for agonistic and antagonistic activity. Eur J Biochem. 2000; 267: 3032-3039.
71. Inagawa H, Kohchi C, Soma G. Oral administration of lipopolysaccharides for the prevention of various diseases: benefit and usefulness. Anticancer Res. 2011; 31: 2431-2436.
72. Gantke T, Sriskantharajah S, Ley SC. Regulation and function of TPL-2, an IκB kinase-regulated MAP kinase kinase kinase. Cell Res. 2011; 21: 131-145.
73. Gupta SC, Sundaram C, Reuter S, Aggarwal BB. Inhibiting NF-κB activation by small molecules as a therapeutic strategy. Biochim Biophys Acta. 2010; 1799: 775-787. 74. Landstrom M. The TAK1-TRAF6 signalling pathway. Int J Biochem Cell Biol. 2010; 42: 58558-58559.
75. Li X, Jiang S, Tapping RI. Toll-like receptor signaling in cell proliferation and survival. Cytokine. 2010; 49: 1-9.
76. Liu S, Chen ZJ. Expanding role of ubiquitination in NF-κB signaling. Cell Res. 2011; 21: 6-21.
77. Liu SF, Malik AB. NF-κB activation as a pathological mechanism of septic shock and inflammation. Am J Physiol. 2006; 290: 622-645.
78. Oeckinghaus A, Ghosh S. The NF-kappaB family of transcription factors and its regulation. Cold Spring Harb Perspect Biol. 2009; 1: a000034.
79. Nijland R, Hofland T, van Strijp JAG. Recognition of LPS by TLR4: Potential for anti-inflammatory therapies. Mar Drugs. 2014; 12: 4260- 4273.
80. Wertz IE, Dixit VM. Signaling to NF-κB: regulation by ubiquitination. Cold Spring Harb Perspect Biol. 2010; 2: a003350.
81. Wittebole X, Castanares-Zapatero D, Laterre PF. Toll-like receptor 4 modulation as a strategy to treat sepsis. Mediators Inflamm. 2010; 2010: 568396.
82. Wiel E, Lebuffe G, Robin E, Gasan G, Corseaux D, Tavernier B, Jude B, Bordet R, Vallet B. Pretreatment with peroxysome proliferator-activated receptor α agonist fenofibrate protects endothelium in rabbit Escherichia coli endotoxininduced shock. Intens Care Med. 2005; 31: 1269-1279.
83. Wu WT, Lee CC, Lee CJ, Subeq YM, Lee RP, Hsu BG. Rosiglitazone ameliorates endotoxin-induced organ damage in conscious rats. Biol Res Nursing. 2011; 13: 38-43.
84. Kaplan JM, Cook JA, Hake PW, O’Connor M, Burroughs TJ, Zingarelli B. 15-Deoxy-[Delta]12,14-prostaglandin J2 (15D-PGJ2), a peroxisome proliferator activated receptor γ ligand, reduces tissue leukosequestration and mortality in endotoxic shock. Shock. 2005; 24: 59-65.