LAPORAN PENELITIAN HIBAH BERSAING TAHUN ......SUMMARY Metabolic syndrome (MetS) is a cluster of...
Transcript of LAPORAN PENELITIAN HIBAH BERSAING TAHUN ......SUMMARY Metabolic syndrome (MetS) is a cluster of...
LAPORAN PENELITIAN HIBAH BERSAING
TAHUN ANGGARAN 2011
PROFILIN SEBAGAI BIOMARKER DISFUNGSI ADIPOSIT (STUDI HUBUNGAN
DISFUNGSI ADIPOSIT DENGAN INFEKSI Toxoplasma gondii
PADA INDIVIDU OBESE)
o leh:
dr. Agustin Iskandar, MKes
Prof.DR.dr. M Rasyad Indra, MS
Satuman,S.Si, MKes
Dib iayai O leh Dire ktorat Jenderal P endidika n Tinggi, Kementrian Pendidikan Nasional,
melalui DIPA Univers itas Brawijaya Rev.1 Nomor : 0636/023-04.2.16/15/20 11 R, tanggal
30 Mare t 2011, dan berda sarkan Surat dari DP2M Dikt i Nomor: 121/D3/PL/2011
tanggal 7 Februari 2011
UNIVERSITAS BRAWIJAYA
NOPEM BER 2011
KESEHATAN
RINGKASAN
Sindroma metabolik merupakan kumpulan beberapa faktor resiko seperti hipertensi,
dislipidemia, gangguan toleransi glukosa dan obesitas. Sindroma ini memiliki hubungan dengan
mekanisme patologis penyakit kardiovaskuler. Obesitas yang menjadi faktor resiko sindroma
metabolik pada umumnya obesitas abdominal atau obesitas viseral. Prevalensi obesitas di
seluruh dunia dan hubungannya dengan kelompok penyakit metabolik meningkat dengan cepat.
Di Amerika Serikat 65,7% dewasa dan 16% anak-anak mengalami overweight (Tuncman, et al.,
2006; http://www.americanheart.org). Angka obesitas terus meningkat dari tahun ke tahun.
Laporan WHO tahun 2003 menyebutkan, di dunia lebih dari 300 juta orang dewasa menderita
obesitas. Di Amerika 280.000 orang meninggal setiap tahunnya akibat obesitas karena menjadi
pemicu penyakit-penyakit seperti jantung, artritis, DM tipe 2 serta tekanan darah tinggi (Rajala,
et al., 2003).
Sampai saat ini peranan infeksi profilin dari parasit T. gondii dalam hubungannya
dengan disfungsi adiposit belum banyak diketahui. Toxoplasma gondii merupakan parasit
patogen intraseluler yang memiliki kemampuan untuk menginfeksi semua sel berinti mamalia
(Olgica D and Vladimir M, 2001). T gondii memiliki molekul profilin yang berhubungan dengan
infeksi pada sel host melalui aktivasi TLRs. Penelitian yang dilakukan Sudjari, dkk. (2009)
memperoleh hasil bahwa; (1) paparan profilin T.gondii pada kultur sel lemak subkutan dapat
meningkatkan kadar IL-6 dan TNF-α serta menurunkan kadar TLR-11, dan (2) peningkatan
kadar IL-6 dan TNF-α pada lemak subkutan mengindikasikan terjadinya adiposopati dan
sindroma metabolik akibat infeksi profilin T.gondii.
Penelitian ini bertujuan untuk mengetahui kadar profilin T gondii pada individu obese,
dibandingakan dengan individu yang tidak obese, serta mengetahui hubungan antara kadar
profilin T gondii dengan ekspresi IL-6 dan IL-12 pada individu obese. Dengan diketahuinya
kadar profilin, IL-6 dan IL-12 pada individu obese, didapatkan gambaran keterlibatan disfungsi
adiposit pada patomekanisme sindroma metabolik akibat infeksi protozoa parasit.
Penelitian ini adalah penelitian observasional analitik dengan desain cross sectional
study. Subyek dalam penelitian ini adalah 65 individu obese dan 10 individu sehat sebagai
pembanding. Setelah melalui wawancara, dilakukan pemeriksaan antropometri dan panel
sindroma metabolik. Pengukuran kadar profilin, IL-6 dan IL-12 dilakukan menggunakan metode
ELISA.
Hasil penelitian pada 65 individu obese didapatkan rerata kadar profilin yang berbeda
bermakna bila dibandingkan dengan individu yang tidak obese (p= 0,001; α= 0,05). Hal ini
menunjukkan bahwa adanya infeksi oleh Toxoplasma gondii akan meningkatkan ekspresi
profilin yang dibutuhkan untuk invasi parasit pada sel host, termasuk sel lemak. Ikatan profilin-
like protein dengan TLR-11 selanjutnya akan meningkatkan ekspresi sitokin proinflamasi yang
berakibat meningkatnya inflamasi pada adiposit sehingga timbul adipositopati dan obesity.
Hasil yang seiring ditunjukkan oleh IL-12, yakni terdapat perbedaan kadar IL-12 yang
bermakna antara individu obese dengan individu sehat(p=0,001, α=0,05). Hal ini dapat terjadi
karena pada individu obese, terjadi peningkatan ekspresi adipositokin termasuk IL-12 sebagai
sitokin proinflamasi. Hasil penelitian ini sejalan dengan peningkatan profilin yang bermakna
pada individu obese. Adanya peningkatan ekspresi profilin akan meningkatkan ekspresi IL-12
sebagai akibat ikatan profilin dengan TLR-11 pada membran adiposit. Selanjutnya ikatan ini
melalui MyD88-pathway akan merangsang ekspresi inflamatory cytokine termasuk IL-12.
Hasil uji independent t test untuk rerata kadar IL-6 menunjukkan bahwa tidak terdapat
perbedaan kadar IL-6 yang bermakna antara individu obese dengan individu sehat (p=0,068,
α=0,05). Hal ini diduga disebabkan karena IL-6 bukan satu-satunya sitokin yang meningkat
pada obesitas. Terdapat sitokin lain seperti TNF-α yang juga meningkat
Penelitian lebih lanjut diperlukan untuk mengetahui hubungan antara peningkatan kadar
profilin dengan adipositokin lain sehingga lebih bisa menjelaskan patomekanisme terjadinya
disfungsi adiposit akibat infeksi parasit Toxoplasma gondii.
SUMMARY
Metabolic syndrome (MetS) is a cluster of various clinicalcardiovascular risk factors
including obesity, dyslipidemia and hypertension, and is characterized by high fasting circulating
insulin levels. This syndrome have relationship with pathologic mechanism of cardiovascular
diasease. Obesity, especially abdominal or visceral obesity is one of risk factor of metabolic
syndrome. The prevalence of obesity and the relationship with metabolic syndrome is increase
around the world. WHO reported that over 300 million of adult was suffer from obesity, and this
will be increase year by year.
The role of profilin infection by Toxoplasma gondii parasit in relation with adipocyt
dysfunction is unclear until now. Toxoplasma gondii is intracelluler pathogenic parasit which
able to infect all of nucleated cells, include adipocyte. T gondiihave profilin molecule which
correlate with invasion to host cells by activating TLRs. Study by Sudjari et.al,showed that
exposure with profilin of T.gondiiin sub cutaneous adipocyt cells can increase the level of IL-6
and TNF-α . This exposure can also decrease the level of TLR-11, so they conclude that
increasing level of IL-6 and TNF-α in subcutaneous adipocyt indicate that there was
adipocytopathy and metabollic syndrome as a result of profilin infection ofT.gondii.
This study was conducted to know the level of Toxoplasma gondii profilin in obese
patient, compared to healthy subject. This study also conducted to know the level of IL-6 and IL-
12 as inflammatory cytokine and to know the relationship between T gondii profilin and the level
of IL-6 and IL-12 in obese patient.
This study was observational analytic using cross sectional design. The subjects were
65 obese patients and 10 healthy patients. After some interview, the subjects were performed
antropometric measurement and then performed metabolic syndrome panel. The level of
profilin, IL-6 and IL-12 was performed by using ELISA method.
The result showed that there was significant difference of provilin level in obese patients
compared to healthy patients (p= 0,001; α= 0,05). This result show that infection by Toxoplasma
gondiiwill increase profilin expression which needed to parasit invasion to host cell, including
adipocyt cell. The binding of protein-like profilin of Toxoplasma gondii with TLRs followed by
increasing inflammatory cytokine in adipocyt resulting adipositopathy and obesity.
Similar result was shown for IL-12, in which significant difference of IL-12 level was
noted between obese and healthy groups (p=0.001, α=0.05). This might occured
becauseincreased expression of adipositokin, including IL-12, as one of proinflammatory
cytokines in individu with obesity. This current result was appropiate to significant increase of
profilin in obese individu. Increased expression of profilin results in increased expression of IL-
12 as a consequence of profilin binding to TLR-11 on adipocyt membrane. Further more, this
binding stimulate expressions of inflammatory cytokines, including IL-12, through MyD88-
pathway.
Independent t test for mean of IL-6 level revealed no significant difference of IL-6 level
between obese and healthy group(p=0.068, α=0.05). This is thought because that IL-6 is not
only cytokine increased in obesity. Other cytokines such as TNF-α is also increased.
Further research is needed to understand the relationship between increasing profilin level and
other adipocytokines so that there will be more explainable pathomechanism of adipocyt
dysfunction secondary to Toxoplasma gondii infection
DAFTAR PUSTAKA
Atsushi Tsuchida, Toshimasa Yamauchi, Sato Takekawa, Yusuke Hada, Yusuke Ito, Toshiyuki
Maki, and Takashi Kadowaki. 2005. Peroxisome Proliferator–Activated Receptor
(PPAR)γActivation Increases Adiponectin Receptors and Reduces Obesity-Related
Inflammation in Adipose Tissue. Diabetes 54:3358–3370
Audra J. Charron and L. David Sibley. 2002. Host cells: mobilizable lipid resources for the
intracellular parasite Toxoplasma gondii. Journal of Cell Science 115, 3049-3059
Bays H, Abate N, Chandalia M. 2005. Adiposopathy: Sick fat causes high blood sugar, high
blood pressure, and dyslipidemia. Future Cardiology 1 (1): 39–59.
Bays H, Dujovne CA. 2006. Adiposopathy is a more rational treatment target for metabolic
disease than obesity alone. Curr Atheroscler Rep 8 (2): 144–56.
Bays H, Lawrence B and Robert R. 2008. Adiposopathy: how do diet, exercise and weight loss
drug therapies improve metabolic disease in overweight patients?. Expert Review of
Cardiovascular Therapy. Vol. 4, No. 6, Pages 871-895.
Berg, Anders H., Ying Lin, Michael P. Lisanti, and Philipp E. Scherer. 2004. Adipocyte
differentiation induces dynamic changes in NF-κB expression and activity. Am J Physiol
Endocrinol Metab 287: E1178–E1188.
Bozaoglu K, Bolton K, McMillan J, Zimmet P, Jowett J, Collier G, et al. 2007. Chemerin is a
novel adipokine associated with obesity and metabolic syndrome. Endocrinology
148:4687-94.
Chen M, Aosai F, Norose K, Mun H-S, Takeuchi O, Akira S, and Yano A. 2002. Involvement
of MyD88 in Host Defense and the Down-Regulation of Anti-Heat Shock Protein 70
Autoantibody Formation by MyD88 in Toxoplasma gondii-Infected Mice. The Journal
of Parasitology, Vol. 88, No. 5, pp. 1017-1019
Cheng-Hu Liu, Fabiana SM, Rishu G, Nichols KE, Burks AW, Aliberti JC, and Xiao-Ping
Zhong. 2007. Diacylglycerol kinase ζ regulates microbial recognition and host resistance
to Toxoplasma gondii. JEM The Rockefeller University Press Vol. 204, No. 4: 781–792
Corsonello A, Perticone F, Malara A, De Domenico D, Loddo S, Buemi M, et al. (2003). Leptin-
dependent platelet aggregation in healthy, overweight and obese subjects. Int J Obes 27:
566-573.
Creely. J. S, Philip Gerard Mc.T, Christine M. K., folliot , M. F, Manish K., Mark E., Alison
.l. H., and Sudhesh K. 2006. Lipopolysaccharide activates an innate immune system
response in human adipose tissue in obesity and type 2 diabetes. Am J Physiol Endocrinol
Metab.
Dharmana, Edi. 2007. Toxoplasma gondii ; Musuh Dalam Selimut. Pidato pengukuhan pada
Upacara Penerimaan Jabatan Guru Besar Parasitologi Fakultas Kedokteran Universitas
Diponegoro.
Desruisseaux, S. M., Nagajyothi, Maria, E. T., Herbert, B. T., and Phillip, E. S. 2007. Adipocyte,
Adipose Tissue, and Infectious Disease. Infection and Immunity, Vol. 75 No. 3: 1066-1078
Fanny N. Lauw, Daniel R. Caffrey and Douglas T. Golenbock. 2005. Of mice and man: TLR11
(finally) finds profilin. Trends in Immunology, Vol. 26, Issue 10: 509-511
Dhurandhar NV. 2001. Infectobesity: Obesity of Infectious Origin. J. Nutr. 131: 2794S–2797S
Ford ES, Giles WH, Dietz WH. 2002. Prevalence of the metabolic syndrome among US adults:
findings from the third National Health and Nutrition Examination Survey. Journal of
American Medical Association. Jan 16;287(3):356-9.
Francoise Debierre-Grockiego, Khamran Rabi, Jörg Schmidt, Hildegard Geyer, Rudolf Geyer,
and Ralph T. Schwarz. 2007. Fatty acids isolated from Toxoplasma gondii reduce GPI-
induced TNFαproduction through inhibition of NF-κB signaling pathway. Infect. Immun. 10.
1128.
Frederic P, Denis A, Denis R, and Yves D. 2002. Responses of Adipose and Muscle Lipoprotein
Lipase to Chronic Infection and Subsequent Acute Lipopolysaccharide Challenge. Clinical
and Diagnostic Laboratory Immunology, Vol. 9, No. 4 , p. 771–776
Fruhbeck, G., Ambrozi, G. J., Muruzabal, J. F., and Burrel, M. A., 2001. The Adipocyte: a Model
for Integration of Endocrine and Metabolic signaling in Energy Metabolism Regulation, Am
J Physiol Endocrinol Metab. 280: issue 6, E827-847.
Godefroy OP, Lecoeur C, Pattou F, Fruhbeck G, et al. 2008. Inflammation is associated with a
decrease of lipogenic factors in omental fat in women. American Journal of
Physiology,doi:10.1152/ajpregu.00926.2007.
Grundy SM, Cleeman JI, Bairey Merz CN, et al. 2004. The Coordinating Committee of the
National Cholesterol Education Program, Implication of recent clinical trials for the National
Cholesterol Education Program Adult Treatment Panel III Guidelines. Circulation,
2004;110:227-239.
Grundy SM. 2006. Metabolic syndrome: connecting and reconciling cardiovascular and diabetes worlds. J Am CollCardiol. 21;47(6):1093-100.
Guilherme A, Virbasius JV, Puri V, Czech MP. 2008. Adipocyte dysfunctions linking obesity to
insulin resistance and type 2 diabetes, Nature Reviews 9:367-377
Hoelson E. S., Lee. J., and Goldfine B. A., 2006. Inflamation and Insulin Resistance. J. Clin
Invest. 116: 1793-1801.
Haunerland NH, Spener F. 2004. Fatty acid-binding proteins--insights from genetic
manipulations. Prog Lipid Res. 2004 Jul;43(4):328-49.
Hung J, McQuillan BM, Thompson PL, Beilby JP. (2008). Circulating adiponectin levels
associate with infalmatory markers, insulin resistance and metabolis syndrome
independent of obesity, Int J Obes 32:772-779
Hye-Seong Mun, Fumie Aosai, Kazumi Norose, Mei Chen, et al. 2003. TLR2 as an essential
molecule for protective immunity against Toxoplasma gondii infection. International
Immunology, Vol. 15, No. 9, pp. 1081-1087.
Junqueira, LC., and Carneiro, J. 2005. "Basic Histology:Text and Atlas". 12th ed. The McGraw-
Hill Companies. New York.
Jia, KS. Xiang, L. Chean, JX. Lu and YM. Wu. 2002. Epidemiological study on obesity and its
comorbidities in urban Chinese older than 20 years of age in Shanghai, China. Obesity
Reviews, 3: 157- 165.
Kawai, T and Akira, S. 2006. TLR signaling. Cell Death and Differentiation,13, 816–825
Kim S, Moustaid-Moussa N. 2000. Secretory, endocrine and autocrine/paracrine function of the
adipocyte, J Nutr 130: 3110S-3115S.
Knoll, Laura. 2010. Understanding the Connection Between the Human Microbiota, Metabolism,
and Obesity. Medical Microbiology & Immunology. FRI 2010 Annual Spring Meeting, May
18, 2010. Food Research Institute, University of Wisconsin-Madison, fri.wisc.edu.
Laporan Hasil Riset Kesehatan Dasar (RISKESDAS) Nasional. 2007. Badan Penelitian dan
Pengembangan Kesehatan Indonesia.
Lehrke. M and Lazar A. M. 2004. Inflamed about Obesity. Nature Medicine. Vol.10 No.2 pp: 6-7
Low S, Chin MC, Deurenberg-Yap M. 2009. Review on epidemic of obesity. Ann Acad Med
Singapore 2009;38:57-65
Lustig RH, Sen, Soberman JE, Velasquez-Mieyer, (2004). Obesity, leptin resistance, and the
effects of insulin reduction, Int Jl of Obes 28: 1344-1348
Lyon. J. C., Law. E. R., And Hsueh. W. Adiposity, Inflammation, and Atherogenesis. 2003.
Endocrinology 144: 2195–2200.
Makowski L, Hotamisligil GS. 2004. Fatty acid binding proteins—the evolutionary crossroads of
inflammatory and metabolic responses. J Nutr 2004;134:2464S–2468S.
Makowski L, Hotamisligil GS. 2005. The role of fatty acid binding proteins in metabolic
syndrome and atherosclerosis. Curr. Opin. Lipidol.16 (5): 543–8.
Musri MM, Gomis R, Parrizas M. 2007. Chromatin and chromatin-modifying proteins in
adipogenesis. Biochem Cell Biol 85: 397-410.
Olgica D and Vladimir M. 2001. Murine Model of Drug-induced Reactivation of Toxoplasma
gondii. Acta Protozool. 40: 99 - 106
Delerive P, Fruchart JC and Staels B. 2001. Peroxisome proliferator-activated receptors in
inflammation control. Journal of Endocrinology 169, 453–459
Pe’russe, L., Chagnon, YC., Weisnagel, J. (2001). The human obesity gene map: the 2000
update, Obes Res 9:135-169.
Plattner, F., Yarovinsky, F., Romero S., Didry D., Carlier M.F., Sher A., Soldatifavre D. 2008.
Toxoplasma Profilin is essential for host cells invasion and TLR-11-dependent induction of
an Interleukin-12 Response. Cell Host Microbe, 3 (2): 77-87
Rajala. W. M. And Scherer. E. P., 2003. Minireview: The Adipocyte—At the Crossroads of
Energy. Homeostasis, Inflammation, and Atherosclerosis. Endocrinology 144: 3765–3773
Robert C. 2002. The role of PPARs in inflammation and immunity. J. Leukoc.Biol. 71: 388–400
Robben, PM., Mordue DG, Truscott SM, Takeda K, Akira S, and Sibley LD. 2004. Production
of IL-12 by Macrophages Infected with Toxoplasma gondii Depends on the Parasite
Genotype. The Journal of Immunology, 2004, 172: 3686–3694
Rosen ED, MacDougall OA. 2006. Adipocyte differentation from the inside out. Nat Rev Mol
Cell Biol 2006;7:885-896.
Rosen ED. 2002. The molecular control of adipogenesis, with special reference to lymphatic
pathology, Ann N Y Acad Sci 979: 143-58
Sattar N, Gaw A, Scherbakova O, Ford I, et al. 2003.Metabolic Syndrome With and Without C-
Reactive Protein as a Predictor of Coronary Heart Disease and Diabetes in the West of
Scotland Coronary Prevention Study. Circulation 2003, 108:414-419
Sargowo, Djanggan.,Andarini, Sri., dkk., 2011. The Relationship Between Food Intake and Adolescent Metabolic Syndrome. JurnalKardiologi Indonesia.Vol. 32, No.1, hal 14-23.ISSN 0126/3773.
Simón I, Escoté X, Vilarrasa N, José Gómez, et al. 2009. Adipocyte Fatty Acid-binding Protein
as a Determinant of Insulin Sensitivity in Morbid-obese Women. Obesity (2009) 17, 1124–
1128. doi:10.1038/oby.2008.665
Soegondo S. 2004. Metabolic syndrome: Fight for it. 3rd National Obesity Symposium. hal : 31-
41, ISSN 1412-6672.
Sudjari, Indra R, Susanto H. 2009. The Effect of Toxoplasma gondii Profilin Induction on the
Expression of TLR-11, IL-6, and TNF- α as a Predictor Candidate of Adipocyte
Dysfunction (invitro Study Adipocyte Dysfunction on Subcutan Adipocyte Culture).
SEMNAS MIPA 2010.
Suplicy H, Bornschein A. 2009. Infeccions as the etiology for obesity. Arq Bras Endocrinol
Metab. 2009;53(2):159-164.
Sul HS, Smas C, Mei B, Zhou L. 2000. Function of pref-1 as an inhibitor of adipocyte
differentiation, Int J Obes 24 (Suppl 4): S15-S19.
Takayoshi Suganami, Kanami Tanimoto-Koyama, Junko Nishida, Michiko Itoh, Xunmei Yuan,
Shinji Mizuarai, Hidehito Kotani, Shoji Yamaoka, Kensuke Miyake, Seiichiro Aoe,
Yasutomi Kamei, Yoshihiro Ogawa. 2007. Role of the Toll-like Receptor 4/NF-κB Pathway
in Saturated Fatty Acid–Induced Inflammatory Changes in the Interaction Between
Adipocytes and Macrophages. Arterioscler Thromb Vasc Biol. 27:84-91
Tchernof A. 2007. Visceral adipocytes and metabolic syndrome. Nutr Rev 65: S24-S30.
Valsamakis G, McTernan PG, Chetty R, Al Daghri N, Field A, Hanif W, Barnett AH, and Kumar
S. 2004. Modest weight loss and reduction in waist circumference after medical treatment
are associated with favorable changes in serum adipocytokines. Metabolism 53: 430–434.
Xu A, Wang Y, Yu Xu J, Stejskal D, et al. 2006. Adipocyte Fatty Acid–Binding Protein Is a
Plasma Biomarker Closely Associated with Obesity and Metabolic Syndrome. Clinical
Chemistry52:3: 405–413.
Yarovinsky F, ZhangD, AndersenJF, Bannenberg GL, et al. 2005. TLR-11 activation of dendritic
cells by a protozoan profilin-like protein. Science: Vol. 308 no. 5728 pp. 1626-1629.