DOI QR코드

DOI QR Code

Lipopolysaccharide-binding protein plasma levels as a biomarker of obesity-related insulin resistance in adolescents

  • Kim, Ki Eun (Department of Pediatrics, CHA Gangnam Medical Center, CHA University School of Medicine) ;
  • Cho, Young Sun (Department of Pediatrics, CHA Bundang Medical Center, CHA University School of Medicine) ;
  • Baek, Kyung Suk (Department of Pediatrics, CHA Gangnam Medical Center, CHA University School of Medicine) ;
  • Li, Lan (Department of Biomedical Science, CHA Bundang Medical Center, CHA University School of Medicine) ;
  • Baek, Kwang-Hyun (Department of Biomedical Science, CHA Bundang Medical Center, CHA University School of Medicine) ;
  • Kim, Jung Hyun (Atmin Radiology and Health Promotion Center) ;
  • Kim, Ho-Seong (Department of Pediatrics, Severance Children's Hospital, Yonsei University College of Medicine) ;
  • Sheen, Youn Ho (Department of Pediatrics, CHA Gangnam Medical Center, CHA University School of Medicine)
  • Received : 2015.09.03
  • Accepted : 2015.12.02
  • Published : 2016.05.15

Abstract

Purpose: Lipopolysaccharide-binding protein (LBP) is a 65-kDa acute phase protein, derived from the liver, which is present in high concentrations in plasma. Data regarding the association between circulating plasma LBP levels and obesity-related biomarkers in the pediatric population are scarce. We aimed to determine whether there was a difference in plasma LBP levels between overweight/obese and normal-weight adolescents and to assess the correlation of circulating LBP levels with anthropometric measures and obesity-related biomarkers, including insulin resistance, liver enzyme levels, and lipid profiles. Methods: The study included 87 adolescents aged 12-13 years; 44 were overweight/obese and 43 were of normal-weight. We assessed anthropometric and laboratory measures, including body mass index (BMI), blood pressure, insulin resistance, liver enzyme levels, and lipid profiles. Plasma LBP levels were measured using an enzyme-linked immunosorbent assay. Results: The mean age of the participants was $12.9{\pm}0.3$ years. Circulating plasma LBP levels were significantly increased in overweight/obese participants compared with those in normal-weight participants ($7.8{\pm}1.9{\mu}g/mL$ vs. $6.0{\pm}1.6{\mu}g/mL$, P<0.001). LBP levels were significantly and positively associated with BMI, systolic blood pressure, aspartate aminotransferase, alanine aminotransferase, total cholesterol, low density lipoprotein-cholesterol, fasting glucose and insulin, and insulin resistance as indicated by the homeostatic model assessment of insulin resistance (HOMA-IR) (all P<0.05). In multivariate linear regression analysis, BMI and HOMA-IR were independently and positively associated with plasma LBP levels. Conclusion: LBP is an inflammatory biomarker associated with BMI and obesity-related insulin resistance in adolescents. The positive correlation between these parameters suggests a potentially relevant pathophysiological mechanism linking LBP to obesity-related insulin resistance in adolescents.

Keywords

References

  1. Huffman MD, Capewell S, Ning H, Shay CM, Ford ES, Lloyd- Jones DM. Cardiovascular health behavior and health factor changes (1988-2008) and projections to 2020: results from the National Health and Nutrition Examination Surveys. Circulation 2012;125:2595-602. https://doi.org/10.1161/CIRCULATIONAHA.111.070722
  2. Reilly JJ, Kelly J. Long-term impact of overweight and obesity in childhood and adolescence on morbidity and premature mortality in adulthood: systematic review. Int J Obes (Lond) 2011;35:891-8. https://doi.org/10.1038/ijo.2010.222
  3. Adams KF, Schatzkin A, Harris TB, Kipnis V, Mouw T, Ballard- Barbash R, et al. Overweight, obesity, and mortality in a large prospective cohort of persons 50 to 71 years old. N Engl J Med 2006;355:763-78. https://doi.org/10.1056/NEJMoa055643
  4. de Heredia FP, Gomez-Martinez S, Marcos A. Obesity, inflammation and the immune system. Proc Nutr Soc 2012;71:332-8. https://doi.org/10.1017/S0029665112000092
  5. Tremaroli V, Backhed F. Functional interactions between the gut microbiota and host metabolism. Nature 2012;489:242-9. https://doi.org/10.1038/nature11552
  6. Shen J, Obin MS, Zhao L. The gut microbiota, obesity and insulin resistance. Mol Aspects Med 2013;34:39-58. https://doi.org/10.1016/j.mam.2012.11.001
  7. Gonzalez-Quintela A, Alonso M, Campos J, Vizcaino L, Loidi L, Gude F. Determinants of serum concentrations of lipopolysaccharide- binding protein (LBP) in the adult population: the role of obesity. PLoS One 2013;8:e54600. https://doi.org/10.1371/journal.pone.0054600
  8. Luoto R, Kalliomäki M, Laitinen K, Delzenne NM, Cani PD, Salminen S, et al. Initial dietary and microbiological environments deviate in normal-weight compared to overweight children at 10 years of age. J Pediatr Gastroenterol Nutr 2011;52:90-5. https://doi.org/10.1097/MPG.0b013e3181f3457f
  9. Moreno-Navarrete JM, Ortega F, Serino M, Luche E, Waget A, Pardo G, et al. Circulating lipopolysaccharide-binding protein(LBP) as a marker of obesity-related insulin resistance. Int J Obes(Lond) 2012;36:1442-9. https://doi.org/10.1038/ijo.2011.256
  10. Wan Y, Freeswick PD, Khemlani LS, Kispert PH, Wang SC, Su GL, et al. Role of lipopolysaccharide (LPS), interleukin-1, interleukin-6, tumor necrosis factor, and dexamethasone in regulation of LPSbinding protein expression in normal hepatocytes and hepatocytes from LPS-treated rats. Infect Immun 1995;63:2435-42.
  11. Su GL, Freeswick PD, Geller DA, Wang Q, Shapiro RA, Wan YH, et al. Molecular cloning, characterization, and tissue distribution of rat lipopolysaccharide binding protein. Evidence for extrahepatic expression. J Immunol 1994;153:743-52.
  12. Moreno-Navarrete JM, Escote X, Ortega F, Serino M, Campbell M, Michalski MC, et al. A role for adipocyte-derived lipopolysaccharide-binding protein in inflammation- and obesity-associated adipose tissue dysfunction. Diabetologia 2013;56:2524-37. https://doi.org/10.1007/s00125-013-3015-9
  13. Grube BJ, Cochane CG, Ye RD, Green CE, McPhail ME, Ulevitch RJ, et al. Lipopolysaccharide binding protein expression in primary human hepatocytes and HepG2 hepatoma cells. J Biol Chem 1994;269:8477-82.
  14. Ghanim H, Abuaysheh S, Sia CL, Korzeniewski K, Chaudhuri A, Fernandez-Real JM, et al. Increase in plasma endotoxin concentrations and the expression of Toll-like receptors and suppressor of cytokine signaling-3 in mononuclear cells after a high-fat, highcarbohydrate meal: implications for insulin resistance. Diabetes Care 2009;32:2281-7. https://doi.org/10.2337/dc09-0979
  15. Tobias PS, Soldau K, Ulevitch RJ. Identification of a lipid A binding site in the acute phase reactant lipopolysaccharide binding protein. J Biol Chem 1989;264:10867-71.
  16. Hailman E, Lichenstein HS, Wurfel MM, Miller DS, Johnson DA, Kelley M, et al. Lipopolysaccharide (LPS)-binding protein accelerates the binding of LPS to CD14. J Exp Med 1994;179:269-77. https://doi.org/10.1084/jem.179.1.269
  17. Wurfel MM, Kunitake ST, Lichenstein H, Kane JP, Wright SD. Lipopolysaccharide (LPS)-binding protein is carried on lipoproteins and acts as a cofactor in the neutralization of LPS. J Exp Med 1994;180:1025-35. https://doi.org/10.1084/jem.180.3.1025
  18. Lepper PM, Kleber ME, Grammer TB, Hoffmann K, Dietz S, Winkelmann BR, et al. Lipopolysaccharide-binding protein (LBP) is associated with total and cardiovascular mortality in individuals with or without stable coronary artery disease-- results from the Ludwigshafen Risk and Cardiovascular Health Study (LURIC). Atherosclerosis 2011;219:291-7. https://doi.org/10.1016/j.atherosclerosis.2011.06.001
  19. Liu X, Lu L, Yao P, Ma Y, Wang F, Jin Q, et al. Lipopolysaccharide binding protein, obesity status and incidence of metabolic syndrome: a prospective study among middle-aged and older Chinese. Diabetologia 2014;57:1834-41. https://doi.org/10.1007/s00125-014-3288-7
  20. Sun L, Yu Z, Ye X, Zou S, Li H, Yu D, et al. A marker of endotoxemia is associated with obesity and related metabolic disorders in apparently healthy Chinese. Diabetes Care 2010;33:1925-32. https://doi.org/10.2337/dc10-0340
  21. Moon JS, Lee SY, Nam CM, Choi JM, Choe BK, Seo JW, et al. 2007 Korean National Growth Charts: review of developmental process and an outlook. Korean J Pediatr 2008;51:1-25. https://doi.org/10.3345/kjp.2008.51.1.1
  22. Matthews DR, Hosker JP, Rudenski AS, Naylor BA, Treacher DF, Turner RC. Homeostasis model assessment: insulin resistance and beta-cell function from fasting plasma glucose and insulin concentrations in man. Diabetologia 1985;28:412-9. https://doi.org/10.1007/BF00280883
  23. Shoelson SE, Lee J, Goldfine AB. Inflammation and insulin resistance. J Clin Invest 2006;116:1793-801. https://doi.org/10.1172/JCI29069
  24. Hotamisligil GS, Shargill NS, Spiegelman BM. Adipose expression of tumor necrosis factor-alpha: direct role in obesity-linked insulin resistance. Science 1993;259:87-91. https://doi.org/10.1126/science.7678183
  25. Neels JG, Olefsky JM. Inflamed fat: what starts the fire? J Clin Invest 2006;116:33-5.
  26. Xiao S, Zhao L. Gut microbiota-based translational biomarkers to prevent metabolic syndrome via nutritional modulation. FEMS Microbiol Ecol 2014;87:303-14. https://doi.org/10.1111/1574-6941.12250
  27. Kheirandish-Gozal L, Peris E, Wang Y, Tamae Kakazu M, Khalyfa A, Carreras A, et al. Lipopolysaccharide-binding protein plasma levels in children: effects of obstructive sleep apnea and obesity. J Clin Endocrinol Metab 2014;99:656-63. https://doi.org/10.1210/jc.2013-3327
  28. Challenges in Adolescent Health Care: Workshop Report. 2007. Washington, D.C.: Committee on Adolescent Health Care Services and Models of Care for Treatment, Prevention, and Healthy Development; Board on Children, Youth, and Families; Division of Behavioral and Social Sciences and Education; The National Academies Press; 2009.
  29. Cani PD, Osto M, Geurts L, Everard A. Involvement of gut microbiota in the development of low-grade inflammation and type 2 diabetes associated with obesity. Gut Microbes 2012;3:279-88. https://doi.org/10.4161/gmic.19625
  30. Tilg H, Kaser A. Gut microbiome, obesity, and metabolic dysfunction. J Clin Invest 2011;121:2126-32. https://doi.org/10.1172/JCI58109
  31. Sookoian S, Pirola CJ. Alanine and aspartate aminotransferase and glutamine-cycling pathway: their roles in pathogenesis of metabolic syndrome. World J Gastroenterol 2012;18:3775-81. https://doi.org/10.3748/wjg.v18.i29.3775
  32. Adams LA, Feldstein AE. Nonalcoholic steatohepatitis: risk factors and diagnosis. Expert Rev Gastroenterol Hepatol 2010;4:623-35. https://doi.org/10.1586/egh.10.56
  33. Calcaterra V, Muratori T, Klersy C, Albertini R, Caramagna C, Brizzi V, et al. Early-onset metabolic syndrome in prepubertal obese children and the possible role of alanine aminotransferase as marker of metabolic syndrome. Ann Nutr Metab 2011;58:307-14. https://doi.org/10.1159/000331573
  34. Ruiz AG, Casafont F, Crespo J, Cayón A, Mayorga M, Estebanez A, et al. Lipopolysaccharide-binding protein plasma levels and liver TNF-alpha gene expression in obese patients: evidence for the potential role of endotoxin in the pathogenesis of non-alcoholic steatohepatitis. Obes Surg 2007;17:1374-80. https://doi.org/10.1007/s11695-007-9243-7
  35. Wigg AJ, Roberts-Thomson IC, Dymock RB, McCarthy PJ, Grose RH, Cummins AG. The role of small intestinal bacterial overgrowth, intestinal permeability, endotoxaemia, and tumour necrosis factor alpha in the pathogenesis of non-alcoholic steatohepatitis. Gut 2001;48:206-11. https://doi.org/10.1136/gut.48.2.206

Cited by

  1. Epidemiology of Childhood Obesity in Korea vol.31, pp.4, 2016, https://doi.org/10.3803/enm.2016.31.4.510
  2. Association of gut microbial communities with plasma lipopolysaccharide-binding protein (LBP) in premenopausal women vol.12, pp.7, 2016, https://doi.org/10.1038/s41396-018-0064-6
  3. Increased Serum IGFBP-1 and Reduced Insulin Resistance After Roux-En-Y Gastric Bypass in Chinese Patients with Type 2 Diabetes: a 6-Month Follow-Up vol.28, pp.10, 2018, https://doi.org/10.1007/s11695-018-3242-8
  4. Epidemic obesity in children and adolescents: risk factors and prevention vol.12, pp.6, 2018, https://doi.org/10.1007/s11684-018-0640-1
  5. The level of lipopolysaccharide-binding protein is elevated in adult patients with obstructive sleep apnea vol.18, pp.None, 2016, https://doi.org/10.1186/s12890-018-0647-z
  6. Markers of metabolic endotoxemia as related to metabolic syndrome in an elderly male population at high cardiovascular risk: a cross-sectional study vol.10, pp.None, 2016, https://doi.org/10.1186/s13098-018-0360-3
  7. High intensity interval training promotes total and visceral fat mass loss in obese Zucker rats without modulating gut microbiota vol.14, pp.4, 2016, https://doi.org/10.1371/journal.pone.0214660
  8. Novel associations of serum adropin and lipopolysaccharide-binding protein versus lipid profiles in childhood obesity vol.33, pp.2, 2016, https://doi.org/10.1515/jpem-2019-0329
  9. Novel associations of serum adropin and lipopolysaccharide-binding protein versus lipid profiles in childhood obesity vol.33, pp.2, 2016, https://doi.org/10.1515/jpem-2019-0329
  10. Obesity Reshapes Visceral Fat-Derived MHC I Associated-Immunopeptidomes and Generates Antigenic Peptides to Drive CD8 + T Cell Responses vol.23, pp.4, 2016, https://doi.org/10.1016/j.isci.2020.100977
  11. Biomarkers of cardiometabolic complications in survivors of childhood acute lymphoblastic leukemia vol.10, pp.None, 2020, https://doi.org/10.1038/s41598-020-78493-x
  12. Higher Lipopolysaccharide Binding Protein and Chemerin Concentrations Were Associated with Metabolic Syndrome Features in Pediatric Subjects with Abdominal Obesity during a Lifestyle Intervention vol.13, pp.2, 2016, https://doi.org/10.3390/nu13020289
  13. Association of serum lipopolysaccharide-binding protein level with sensitization to food allergens in children vol.11, pp.1, 2021, https://doi.org/10.1038/s41598-020-79241-x
  14. Investigation of candidate genes and mechanisms underlying obesity associated type 2 diabetes mellitus using bioinformatics analysis and screening of small drug molecules vol.21, pp.1, 2016, https://doi.org/10.1186/s12902-021-00718-5