Nonalcoholic fatty liver disease (NAFLD), one of the most common forms of chronic liver disease, is closely associated with obesity and insulin resistance (IR). Adipokines secreted by adipose tissue have recently been implicated in initiating and perpetuating the chronic inflammatory state observed in obesity and NAFLD. Recent studies suggest neutrophil gelatinase-associated lipocalin (NGAL) plays a key role in the pathogenesis of IR. The aims of this study were to determine urinary NGAL levels in patients with ultrasonography proven NAFLD and to correlate these levels with the metabolic profile and fibrosis grade in this population.
Our cohort consisted of 65 consecutive patients undergoing abdominal ultrasonography for clinical suspicion of NAFLD. Patients were subsequently divided into two groups: no steatosis (n=20) and steatosis (n=45). The stage of fibrosis was measured using a four-point scale. Urinary NGAL was measured by a specific microparticle enzyme immunoassay. The degree of insulin resistance was determined by the homeostatic model assessment (HOMA). Glucose, insulin, lipid profile, and transaminases were also measured.
Urinary NGAL levels correlated with body mass index, HOMA, fasting glucose, and insulin levels in patients with steatosis. Moreover, uNGAL levels were higher in patients with steatosis compared to those with no steatosis (49.8 ng/mL and 22.7 ng/mL, respectively) with a statistically significant difference (p<0.001). A stepwise increase in uNGAL levels from patients without fibrosis (21.7 ng/mL) to patients with cirrhosis (47.4 ng/mL) was noted (p<0.001).
Our study demonstrates that in adult patients with NAFLD, uNGAL levels correlate with BMI, insulin resistance, and lipid profiles, and identifies a novel association between uNGAL levels and hepatocellular injury in these patients.
1. J.C. Seidell 2005 Epidemiology of obesity Semin Vasc Med 5 1 3 14.
2. The World Health Organization (2000): Preventing and managing the global epidemic. In: WHO Technical Report Series 894, Geneva, Switzerland.
3. J.G. Kral F. Schaffner R.N. Pierson J. Wang 1993 Body fat topography as an independent predictor of fatty liver Metabolism 42 5 548 551.
4. G. Ramsey-Stuart 1993 Hepatic steatosis and morbid obesity Obes Surg 3 2 157 159.
5. W. van Steenbergen S. Lanckmans 1995 Liver disturbances in obesity and diabetes mellitus Int J Obes 19 Suppl1 S27 S36.
6. A.M. Wolf B. Busch H.W. Kuhlmann U. Beisiegel 2005 Histological changes in the liver of morbidly obese patients: correlation with metabolic parameters Obes Surg 15 2 228 237.
7. Z.T. Bloomgarden 2005 Second World Congress on the insulin resistance syndrome: hypertension, cardiovascular disease, and treatment approaches Diabetes Care 28 2073 2080.
8. S. Bellentani G. Saccoccio F. Masutti et al.2000 Prevalence of and risk factors for hepatic steatosis in Northern Italy Ann Intern Med 132 2 112 117.
9. J.D. Browning L.S. Szczepaniak R. Dobbins et al.2004 Prevalence of hepatic steatosis in an urban population in the United States: impact of ethnicity Hepatology 40 6 1387 1395.
10. G.V. Papatheodoridis J. Goulis D. Christodoulou et al.2007 High prevalence of elevated liver enzymes in blood donors: associations with male gender and central adiposity Eur J Gastroen Hepat 19 4 281 287.
11. G.C. Farrell C.Z. Larter 2006 Nonalcoholic fatty liver disease: from steatosis to cirrhosis Hepatology 43 2 S99 S112.
12. G. Marchesini E. Bugianesi D. Forlani et al.2003 Nonalcoholic fatty liver, steatohepatitis, and the metabolic syndrome Hepatology 37 4 917 923.
13. E. Tsochatzis G.V. Papatheodoridis E.K. Manesis G. Kafiri D.G. Tiniakos et al.2008 Metabolic syndrome is associated with severe fibrosis in chronic viral hepatitis and non-alcoholic steatohepatitis Aliment Pharm Therap 27 1 80 89.
14. E.A. Tsochatzis S. Manolakopoulos G.V. Papatheodoridis A.J. Archimandritis 2009 Insulin resistance and metabolic syndrome in chronic liver diseases: old entities with new implications Scand J Gastroentero 44 1 6 14.
15. B.R. Bacon M.J. Farahvash C.G. Janney et al.1994 Nonalcoholic steatohepatitis: an expanded clinical entity Gastroenterology 107 1103 1109.
16. C.A. Matteoni Z.M. Younossi T. Gramlich et al.1999 Nonalcoholic fatty liver disease: a spectrum of clinical and pathological severity Gastroenterology 116 1413 1419.
17. A.J. McCullough 2006 Pathophysiology of nonalcoholic steatohepatitis J Clin Gastroenterol 40 Suppl1 S17 S29.
18. L. Kjeldsen A.H. Johnsen H. Sengelov N. Borregaard 1993 Isolation and primary structure of NGAL, a novel protein associated with human neutrophil gelatinase J Biol Chem 268 14 10425 10432.
19. L. Kjeldsen D.F. Bainton H. Sengelov N. Borregaard 1994 Identification of neutrophil gelatinase-associated lipocalin as a novel matrix protein of specific granules in human neutrophils Blood 83 3 799 807.
20. D.R. Flower 1995 The up-and-down beta-barrel proteins: three of a kind FASEB J 9 7 566 567.
21. L.R. Devireddy J.G. Teodoro F.A. Richard M.R. Green 2001 Induction of apoptosis by a secreted lipocalin that is transcriptionally regulated by IL-3 deprivation Science 293 5531 829 834.
22. S.P. Stoesz M.N. Gould 1995 Overexpression of neu-related lipocalin (NRL) in neu-initiated but not ras or chemically initiated rat mammary carcinomas Oncogene 11 11 2233 2241.
23. T.H. Flo K.D. Smith S. Sato D.J. Rodriguez M.A. Holmes R.K. Strong S. Akira A. Aderem 2004 Lipocalin 2 mediates an innate immune response to bacterial infection by sequestrating iron Nature 432 7019 917 921.
24. Q.W. Yan Q. Yang N. Mody T.E. Graham C.H. Hsu Z. Xu N.E. Houstis B.B. Kahn E.D. Rosen 2007 The adipokine lipocalin 2 is regulated by obesity and promotes insulin resistance Diabetes 56 10 2533 2540.
25. Y. Wang K.S. Lam E.W. Kraegen G. Sweeney J. Zhang A.W. Tso W.S. Chow N.M. Wat J.Y. Xu R.L. Hoo et al.2007 Lipocalin-2 is an inflammatory marker closely associated with obesity, insulin resistance, and hyperglycemia in humans Clin Chem 53 1 34 41.
26. I.K. Law A. Xu K.S. Lam T. Berger T.W. Mak P.M. Vanhoutte J.T. Liu G. Sweeney M. Zhou B. Yang et al.2010 Lipocalin-2 deficiency attenuates insulin resistance associated with aging and obesity Diabetes 59 4 872 882.
27. T. Auguet Y. Quintero X. Terra S. Martinez A. Lucas S. Pellitero C. Aguilar M. Hernandez C.D. Del C. Richart 2011 Upregulation of lipocalin 2 in adipose tissues of severely obese women: positive relationship with proinflammatory cytokines Obesity (Silver Spring) 19 12 2295 2300.
28. C.F. Runge 2007 Economic consequences of the obese Diabetes 56 2668 2672.
29. A.A. Bravo S.G. Sheth S. Chopra 2001 Liver biopsy New Engl J Med 344 7 495 500.
30. P. Limanond S.S. Raman C. Lassman et al.2004 Macrovesicular hepatic steatosis in living related liver donors: correlation between CT and histologic findings Radiology 230 276 280.
31. H. Levenson F. Greensite J. Hoefs et al.1991 Fatty infiltration of the liver: quantification with phase-contrast MR imaging at 1.5T vs biopsy AJR Am J Roentgenol 156 307 312.
32. K.J. Taylor F.S. Gorelick A.T. Rosenfield C.A. Riely 1981 Ultrasonography of alcoholic liver disease with histological correlation Radiology 141 157 161.
33. K.J. Mortele P.R. Ros 2001 Imaging of diffuse liver disease Semin Liver Dis 21 2 195 212.
34. C.C. Mottin M. Moretto A.V. Padoin et al.2004 The role of ultrasound in the diagnosis of hepatic steatosis in morbidly obese patients Obes Surg 14 5 635 637.
35. H. Ataseven M.H. Yildirim M. Yalniz H. Bahcecioglu S. Celebi I.H. Ozercan 2005 The value of ultrasonography and computerized tomography in estimating the histopathological severity of nonalcoholic steatohepatitis Acta Gastroenterol Belg 68 221 225.
36. S. Saadeh Z.M. Younossi E.M. Remer et al.2002 The utility of radiological imaging in nonalcoholic fatty liver disease Gastroenterology 123 3 745 750.
37. D. Devarajan 2008 Neutrophil gelatinase-associated lipocalin (NGAL): a new marker of kidney disease Scand J Clin Lab Invest Suppl 241 89 94.
38. E. Tsochatzis G.V. Papatheodoridis A.J. Archimandritis 2006 The evolving role of leptin and adiponectin in chronic liver diseases Am J Gastroentero 101 11 2629 2640.
39. A.S. Greenberg M.S. Obin 2006 Obesity and the role of adipose tissue in inflammation and metabolism Am J Clin Nutr 83 2 461S 465S.
40. Y. Kamada T. Takehara N. Hayashi 2008 Adipocytokines and liver disease J Gastroenterol 43 11 811 822.
41. K.E. Wellen G.S. Hotamisligil 2005 Inflammation, stress, and diabetes J Clin Invest 115 1111 1119.
42. H. Tilg G.S. Hotamisligil 2006 Nonalcoholic fatty liver disease: cytokine-adipokine interplay and regulation of insulin resistance Gastroenterology 131 934 945.
43. K.E. Wellen G.S. Hotamisligil 2003 Obesity-induced inflammatory changes in adipose tissue J Clin Invest 112 1785 1788.
44. S. Wilson N. Chalasani 2007 Noninvasive markers of advanced histology in nonalcoholic fatty liver disease: are we there yet? Gastroenterology 133 1377 1378.
45. Defronzo RA : Dysfunctional fat cells, lipotoxicity and type 2 diabetes. Int J Clin Pract Suppl 9–21 (2004).
46. C. Carter-Kent N.N. Zein A.E. Feldstein 2008 Cytokines in the pathogenesis of fatty liver and disease progression to steatohepatitis: Implications for treatment Am J Gastroenterol 103 1036 1042.
47. S. Chitturi G. Farrell L. Frost et al.2002 Serum leptin in NASH correlates with hepatic steatosis but not fibrosis: a manifestation of lipotoxicity? Hepatology 36 2 403 409.
48. N. Chalasani D.W. Crabb O.W. Cummings et al.2003 Does leptin play a role in the pathogenesis of human nonalcoholic steatohepatitis? Am J Gastroenterol 98 12 2771 2776.
49. P. Angulo L.M. Alba L.M. Petrovic L.A. Adams K.D. Lindor M.D. Jensen 2004 Leptin, insulin resistance, and liver fibrosis in human nonalcoholic fatty liver disease J Hepatol 41 6 943 949.
50. J.M. Hui A. Hodge G.C. Farrell J.G. Kench A. Kriketos J. George 2004 Beyond insulin resistance in NASH: TNF-α or adiponectin? Hepatology 40 1 46 54.
51. G. Musso R. Gambino M. Durazzo et al.2005 Adipokines in NASH: postprandial lipid metabolism as a link between adiponectin and liver disease Hepatology 42 5 1175 1183.
52. E. Cakal M. Ozkaya Y. Engin-Ustun Y. Ustun 2011 Serum lipocalin-2 as an insulin resistance marker in patients with polycystic ovary syndrome J Endocrinol Invest 34 2 97 100.
53. Y. Huang Z. Yang Z. Ye Q. Li J. Wen et al.2010 Lipocalin-2, glucose metabolism and chronic low-grade systemic inflammation in Chinese people Cardiovasc Diabetol 11 11.
54. M. Alvehus J. Buren M. Sjostrom J. Goedecke T. Olsson 2010 The human visceral fat depot has a unique inflammatory profile Obesity (Silver Spring) 18 5 879 883.
55. D.G. Tiniakos M.B. Vos E.M. Brunt 2010 Nonalcoholic fatty liver disease Annu Rev Pathol 5 145 171.
56. D. Van Der Poorten K.L. Milner J. Hui et al.2008 Visceral fat: a key mediator of steatohepatitis in metabolic liver disease Hepatology 48 2 449 457.
57. J. Zhang Y. Wu Y. Zhang D. Leroith D.A. Bernlohr X. Chen 2008 The role of lipocalin 2 in the regulation of inflammation in adipocytes and macrophages Mol Endocrinol 22 6 1416 1426.
58. I. Kratchmarova D.E. Kalume B. Blagoev P.E. Scherer A.V. Podtelejnikov H. Molina P.E. Bickel J.S. Andersen M.M. Fernandez J. Bunkenborg et al.2002 A proteomic approach for identification of secreted proteins during the differentiation of 3 T3-L1 preadipocytes to adipocytes Mol Cell Proteomics 1 3 213 222.
59. H. Cortez-Pinto M.C. de Moura C.P. Day 2006 Non-alcoholic steatohepatitis: from cell biology to clinical practice J Hepatol 44 197 208.
60. V. Ratziu F. Charlotte A. Heurtier et al.2005 Sampling variability of liver biopsy in nonalcoholic fatty liver disease Gastroenterology 128 1898 1906.
61. A. Wieckowska N.N. Zein L.M. Yerian et al.2006 In vivo assessment of liver cell apoptosis as a novel biomarker of disease severity in nonalcoholic fatty liver disease Hepatology 44 27 33.