DOI QR코드

DOI QR Code

Increased Serum Angiopoietin-Like 6 Ahead of Metabolic Syndrome in a Prospective Cohort Study

  • Namkung, Jun (Department of Biochemistry, Yonsei University Wonju College of Medicine) ;
  • Sohn, Joon Hyung (Institute of Lifestyle Medicine, Yonsei University Wonju College of Medicine) ;
  • Chang, Jae Seung (Mitohormesis Research Center, Yonsei University Wonju College of Medicine) ;
  • Park, Sang-Wook (Mitohormesis Research Center, Yonsei University Wonju College of Medicine) ;
  • Kim, Jang-Young (Mitohormesis Research Center, Yonsei University Wonju College of Medicine) ;
  • Koh, Sang-Baek (Mitohormesis Research Center, Yonsei University Wonju College of Medicine) ;
  • Kong, In Deok (Institute of Lifestyle Medicine, Yonsei University Wonju College of Medicine) ;
  • Park, Kyu-Sang (Mitohormesis Research Center, Yonsei University Wonju College of Medicine)
  • Received : 2018.05.16
  • Accepted : 2018.12.21
  • Published : 2019.08.30

Abstract

Background: Despite being an anti-obesity hepatokine, the levels of serum angiopoietin-like 6 (ANGPTL6) are elevated in various metabolic diseases. Thus, ANGPTL6 expression may reflect metabolic burden and may have compensatory roles. This study investigated the association between serum ANGPTL6 levels and new-onset metabolic syndrome. Methods: In total, 221 participants without metabolic syndrome were randomly selected from a rural cohort in Korea. Baseline serum ANGPTL6 levels were measured using an enzyme-linked immunosorbent assay. Anthropometric and biochemical markers were analyzed before and after follow-up examinations. Results: During an average follow-up period of 2.75 (interquartile range, 0.76) years, 82 participants (37.1%) presented new-onset metabolic syndrome and had higher ANGPTL6 levels before onset than those without metabolic syndrome (48.03±18.84 ng/mL vs. 64.75±43.35 ng/mL, P=0.001). In the multivariable adjusted models, the odds ratio for the development of metabolic syndrome in the highest quartile of ANGPTL6 levels was 3.61 (95% confidence interval, 1.27 to 10.26). The use of ANGPTL6 levels in addition to the conventional components improved the prediction of new-onset metabolic syndrome (area under the receiver operating characteristic curve: 0.775 vs. 0.807, P=0.036). Conclusion: Increased serum ANGPTL6 levels precede the development of metabolic syndrome and its components, including low high density lipoprotein, high triglyceride, and high glucose levels, which have an independent predictive value for metabolic syndrome.

Keywords

Acknowledgement

This research was supported by grants from the Korea Centers for Disease Control and Prevention (2010-E71003-00 to SBK) and from the National Research Foundation of Korea funded by the Ministry of Science, ICT & Future Planning (NRF-2017R1A5A2015369 to KSP).

References

  1. Grundy SM. Metabolic syndrome pandemic. Arterioscler Thromb Vasc Biol 2008;28:629-36. https://doi.org/10.1161/ATVBAHA.107.151092
  2. Mottillo S, Filion KB, Genest J, Joseph L, Pilote L, Poirier P, Rinfret S, Schiffrin EL, Eisenberg MJ. The metabolic syndrome and cardiovascular risk a systematic review and meta-analysis. J Am Coll Cardiol 2010;56:1113-32. https://doi.org/10.1016/j.jacc.2010.05.034
  3. Gami AS, Witt BJ, Howard DE, Erwin PJ, Gami LA, Somers VK, Montori VM. Metabolic syndrome and risk of incident cardiovascular events and death: a systematic review and meta-analysis of longitudinal studies. J Am Coll Cardiol 2007;49: 403-14. https://doi.org/10.1016/j.jacc.2006.09.032
  4. Alberti KG, Eckel RH, Grundy SM, Zimmet PZ, Cleeman JI, Donato KA, Fruchart JC, James WP, Loria CM, Smith SC Jr; International Diabetes Federation Task Force on Epidemiology and Prevention; Hational Heart, Lung, and Blood Institute; American Heart Association; World Heart Federation; International Atherosclerosis Society; International Association for the Study of Obesity. Harmonizing the metabolic syndrome: a joint interim statement of the International Diabetes Federation Task Force on Epidemiology and Prevention; National Heart, Lung, and Blood Institute; American Heart Association; World Heart Federation; International Atherosclerosis Society; and International Association for the Study of Obesity. Circulation 2009;120:1640-5. https://doi.org/10.1161/CIRCULATIONAHA.109.192644
  5. Ly LD, Xu S, Choi SK, Ha CM, Thoudam T, Cha SK, Wiederkehr A, Wollheim CB, Lee IK, Park KS. Oxidative stress and calcium dysregulation by palmitate in type 2 diabetes. Exp Mol Med 2017;49:e291. https://doi.org/10.1038/emm.2016.157
  6. Nakatani Y, Kaneto H, Kawamori D, Yoshiuchi K, Hatazaki M, Matsuoka TA, Ozawa K, Ogawa S, Hori M, Yamasaki Y, Matsuhisa M. Involvement of endoplasmic reticulum stress in insulin resistance and diabetes. J Biol Chem 2005;280:847-51. https://doi.org/10.1074/jbc.M411860200
  7. Mota M, Banini BA, Cazanave SC, Sanyal AJ. Molecular mechanisms of lipotoxicity and glucotoxicity in nonalcoholic fatty liver disease. Metabolism 2016;65:1049-61. https://doi.org/10.1016/j.metabol.2016.02.014
  8. Hopps E, Noto D, Caimi G, Averna MR. A novel component of the metabolic syndrome: the oxidative stress. Nutr Metab Cardiovasc Dis 2010;20:72-7. https://doi.org/10.1016/j.numecd.2009.06.002
  9. Mandl J, Meszaros T, Banhegyi G, Hunyady L, Csala M. Endoplasmic reticulum: nutrient sensor in physiology and pathology. Trends Endocrinol Metab 2009;20:194-201. https://doi.org/10.1016/j.tem.2009.01.003
  10. Oike Y, Ito Y, Maekawa H, Morisada T, Kubota Y, Akao M, Urano T, Yasunaga K, Suda T. Angiopoietin-related growth factor (AGF) promotes angiogenesis. Blood 2004;103:3760-5. https://doi.org/10.1182/blood-2003-04-1272
  11. Oike Y, Yasunaga K, Ito Y, Matsumoto S, Maekawa H, Morisada T, Arai F, Nakagata N, Takeya M, Masuho Y, Suda T. Angiopoietin-related growth factor (AGF) promotes epidermal proliferation, remodeling, and regeneration. Proc Natl Acad Sci U S A 2003;100:9494-9. https://doi.org/10.1073/pnas.1531901100
  12. Oike Y, Akao M, Yasunaga K, Yamauchi T, Morisada T, Ito Y, Urano T, Kimura Y, Kubota Y, Maekawa H, Miyamoto T, Miyata K, Matsumoto S, Sakai J, Nakagata N, Takeya M, Koseki H, Ogawa Y, Kadowaki T, Suda T. Angiopoietin-related growth factor antagonizes obesity and insulin resistance. Nat Med 2005;11:400-8. https://doi.org/10.1038/nm1214
  13. Kitazawa M, Ohizumi Y, Oike Y, Hishinuma T, Hashimoto S. Angiopoietin-related growth factor suppresses gluconeogenesis through the Akt/forkhead box class O1-dependent pathway in hepatocytes. J Pharmacol Exp Ther 2007;323:787-93. https://doi.org/10.1124/jpet.107.127530
  14. Oike Y, Akao M, Kubota Y, Suda T. Angiopoietin-like proteins: potential new targets for metabolic syndrome therapy. Trends Mol Med 2005;11:473-9. https://doi.org/10.1016/j.molmed.2005.08.002
  15. Stepan H, Ebert T, Schrey S, Reisenbuchler C, Stein S, Lossner U, Bluher M, Stumvoll M, Kratzsch J, Faber R, Fasshauer M. Serum levels of angiopoietin-related growth factor are increased in preeclampsia. Am J Hypertens 2009;22:314-8. https://doi.org/10.1038/ajh.2008.340
  16. Boztosun A, Deveci K, Klcl F, Soylemez MS, Muhtaroglu S, Muderris II. Serum levels of angiopoietin-related growth factor (AGF) are increased in polycystic ovary syndrome. J Investig Med 2012;60:813-7. https://doi.org/10.231/JIM.0b013e31824e9900
  17. Ebert T, Bachmann A, Lossner U, Kratzsch J, Bluher M, Stumvoll M, Fasshauer M. Serum levels of angiopoietin-related growth factor in diabetes mellitus and chronic hemodialysis. Metabolism 2009;58:547-51. https://doi.org/10.1016/j.metabol.2008.11.016
  18. Ebert T, Kralisch S, Loessner U, Jessnitzer B, Stumvoll M, Fasshauer M, Tonjes A. Relationship between serum levels of angiopoietin-related growth factor and metabolic risk factors. Horm Metab Res 2014;46:685-90. https://doi.org/10.1055/s-0034-1382078
  19. Namkung J, Koh SB, Kong ID, Choi JW, Yeh BI. Serum levels of angiopoietin-related growth factor are increased in metabolic syndrome. Metabolism 2011;60:564-8. https://doi.org/10.1016/j.metabol.2010.05.013
  20. Kim JY, Ahn SV, Yoon JH, Koh SB, Yoon J, Yoo BS, Lee SH, Park JK, Choe KH, Guallar E. Prospective study of serum adiponectin and incident metabolic syndrome: the ARIRANG study. Diabetes Care 2013;36:1547-53. https://doi.org/10.2337/dc12-0223
  21. Choi JR, Kim JY, Park IH, Huh JH, Kim KW, Cha SK, Park KS, Sohn JH, Park JT, Koh SB. Serum fibroblast growth factor 21 and new-onset metabolic syndrome: KoGES-ARIRANG Study. Yonsei Med J 2018;59:287-93. https://doi.org/10.3349/ymj.2018.59.2.287
  22. Lee SY, Park HS, Kim DJ, Han JH, Kim SM, Cho GJ, Kim DY, Kwon HS, Kim SR, Lee CB, Oh SJ, Park CY, Yoo HJ. Appropriate waist circumference cutoff points for central obesity in Korean adults. Diabetes Res Clin Pract 2007;75:72-80. https://doi.org/10.1016/j.diabres.2006.04.013
  23. DeLong ER, DeLong DM, Clarke-Pearson DL. Comparing the areas under two or more correlated receiver operating characteristic curves: a nonparametric approach. Biometrics 1988;44: 837-45. https://doi.org/10.2307/2531595
  24. Galletti F, Barbato A, Versiero M, Iacone R, Russo O, Barba G, Siani A, Cappuccio FP, Farinaro E, della Valle E, Strazzullo P. Circulating leptin levels predict the development of metabolic syndrome in middle-aged men: an 8-year follow-up study. J Hypertens 2007;25:1671-7. https://doi.org/10.1097/HJH.0b013e3281afa09e
  25. Rutter MK, Meigs JB, Sullivan LM, D'Agostino RB Sr, Wilson PW. C-reactive protein, the metabolic syndrome, and prediction of cardiovascular events in the Framingham Offspring Study. Circulation 2004;110:380-5. https://doi.org/10.1161/01.CIR.0000136581.59584.0E
  26. Mora S, Pessin JE. An adipocentric view of signaling and intracellular trafficking. Diabetes Metab Res Rev 2002;18:345-56. https://doi.org/10.1002/dmrr.321
  27. Deurenberg P, Deurenberg-Yap M, Guricci S. Asians are different from Caucasians and from each other in their body mass index/body fat per cent relationship. Obes Rev 2002;3:141-6. https://doi.org/10.1046/j.1467-789X.2002.00065.x
  28. Wang D, Li Y, Lee SG, Wang L, Fan J, Zhang G, Wu J, Ji Y, Li S. Ethnic differences in body composition and obesity related risk factors: study in Chinese and white males living in China. PLoS One 2011;6:e19835. https://doi.org/10.1371/journal.pone.0019835
  29. Roh E, Ko SH, Kwon HS, Kim NH, Kim JH, Kim CS, Song KH, Won JC, Kim DJ, Choi SH, Lim S, Cha BY; Taskforce Team of Diabetes Fact Sheet of the Korean Diabetes Association. Prevalence and management of dyslipidemia in Korea: Korea National Health and Nutrition Examination Survey during 1998 to 2010. Diabetes Metab J 2013;37:433-49. https://doi.org/10.4093/dmj.2013.37.6.433
  30. Kim SM, Han JH, Park HS. Prevalence of low HDL-cholesterol levels and associated factors among Koreans. Circ J 2006;70: 820-6. https://doi.org/10.1253/circj.70.820
  31. Lim S, Shin H, Song JH, Kwak SH, Kang SM, Won Yoon J, Choi SH, Cho SI, Park KS, Lee HK, Jang HC, Koh KK. Increasing prevalence of metabolic syndrome in Korea: the Korean National Health and Nutrition Examination Survey for 1998-2007. Diabetes Care 2011;34:1323-8. https://doi.org/10.2337/dc10-2109
  32. Hong AR, Lim S. Clinical characteristics of metabolic syndrome in Korea, and its comparison with other Asian countries. J Diabetes Investig 2015;6:508-15. https://doi.org/10.1111/jdi.12313
  33. Kim KH, Jeong YT, Oh H, Kim SH, Cho JM, Kim YN, Kim SS, Kim DH, Hur KY, Kim HK, Ko T, Han J, Kim HL, Kim J, Back SH, Komatsu M, Chen H, Chan DC, Konishi M, Itoh N, Choi CS, Lee MS. Autophagy deficiency leads to protection from obesity and insulin resistance by inducing Fgf21 as a mitokine. Nat Med 2013;19:83-92. https://doi.org/10.1038/nm.3014
  34. Kim MJ, Namkung J, Chang JS, Kim SJ, Park KS, Kong ID. Leptin regulates the expression of angiopoietin-like 6. Biochem Biophys Res Commun 2018;502:397-402. https://doi.org/10.1016/j.bbrc.2018.05.180
  35. Kang SG, Yi HS, Choi MJ, Ryu MJ, Jung S, Chung HK, Chang JY, Kim YK, Lee SE, Kim HW, Choi H, Kim DS, Lee JH, Kim KS, Kim HJ, Lee CH, Oike Y, Shong M. ANGPTL6 expression is coupled with mitochondrial OXPHOS function to regulate adipose FGF21. J Endocrinol 2017;233:105-18. https://doi.org/10.1530/10E-16-0549
  36. Ricci PF, Straja SR, Cox AL Jr. Changing the risk paradigms can be good for our health: J-shaped, linear and threshold dose-response models. Dose Response 2012;10:177-89. https://doi.org/10.2203/dose-response.11-020.Ricci

Cited by

  1. Letter: Increased Serum Angiopoietin-Like 6 Ahead of Metabolic Syndrome in a Prospective Cohort Study (Diabetes Metab J 2019;43:521-9) vol.43, pp.5, 2019, https://doi.org/10.4093/dmj.2019.0172
  2. Response: Increased Serum Angiopoietin-Like 6 Ahead of Metabolic Syndrome in a Prospective Cohort Study (Diabetes Metab J 2019;43:521-9) vol.43, pp.5, 2019, https://doi.org/10.4093/dmj.2019.0178
  3. ANGPTL6 Level in Patient with Coronary Heart Disease and Its Relationship with the Severity of Coronary Artery Lesions vol.10, pp.5, 2019, https://doi.org/10.12677/acm.2020.105111
  4. Investigating the Role of Myeloperoxidase and Angiopoietin-like Protein 6 in Obesity and Diabetes vol.10, 2019, https://doi.org/10.1038/s41598-020-63149-7
  5. Effects of Bariatric Surgeries on Fetuin-A, Selenoprotein P, Angiopoietin-Like Protein 6, and Fibroblast Growth Factor 21 Concentration vol.2021, 2019, https://doi.org/10.1155/2021/5527107
  6. Effects of Exercise Intervention on Mitochondrial Stress Biomarkers in Metabolic Syndrome Patients: A Randomized Controlled Trial vol.18, pp.5, 2019, https://doi.org/10.3390/ijerph18052242
  7. 최근 10년간 한국인 대상 대사증후군 예측 모델에 대한 체계적 문헌고찰 vol.21, pp.8, 2019, https://doi.org/10.5392/jkca.2021.21.08.662
  8. Hepatokines and Non-Alcoholic Fatty Liver Disease: Linking Liver Pathophysiology to Metabolism vol.9, pp.12, 2019, https://doi.org/10.3390/biomedicines9121903