NOX2-generated oxidative stress is associated with severity of ultrasound liver steatosis in patients with non-alcoholic fatty liver disease

BMC Gastroenterology

Francesco Angelico¹  Francesco Violi²  Pasquale Pignatelli²  Lorenzo Loffredo²  Francesco Baratta²  Cristina Nocella²  Simona Bartimoccia²  Roberto Carnevale²  Licia Polimeni²  Maria Del Ben² 

[1] I Clinica Medica – Policlinico Umberto I, Viale del Policlinico 155, 00161 Rome, Italy;Department of Internal Medicine and Medical Specialties, Sapienza University, Rome, Italy

关键词: Metabolic syndrome;    sNOX2-dp;    8-iso-PGF2α;    Non-alcoholic fatty liver;    Oxidative stress;   

Others  :  855336
DOI  :  10.1186/1471-230X-14-81

 received in 2013-08-08, accepted in 2014-04-16,  发布年份 2014

【 摘 要 】

Background

Chronic oxidative stress is one of the key mechanisms responsible for disease progression in non-alcoholic fatty liver disease. However, so far, few studies reported increased circulating levels of oxidative stress markers in patients with non-alcoholic fatty liver and no study has been performed with newer markers of systemic oxidative stress. The aim was to assess the relationship between urinary 8-iso-prostaglandin F2α and serum soluble NOX2-derived peptide and the severity of liver steatosis in subjects with non-alcoholic fatty liver.

Methods

The study was performed in 264 consecutive patients referred for suspected metabolic disease. Steatosis was defined according to Hamaguchi ultrasonographic criteria. Oxidative stress was assessed by urinary 8-iso- prostaglandin F2α and serum soluble NOX2-derived peptide levels.

Results

Patients with non-alcoholic fatty liver had higher (p < 0.001) mean values of urinary 8-iso-PGF2α and of serum soluble NOX2-derived peptide, alanine aminotransferase, Cytokeratin-18 and homeostasis model of insulin resistance and lower values of serum adiponectin as compared to those without. Prevalence of metabolic syndrome and of its clinical features was significantly higher in patients with non-alcoholic fatty liver. Same findings were also observed after the exclusion of obese subjects, or subjects with diabetes or with metabolic syndrome and in those not taking statin medication. In addition, the levels of urinary 8-iso-PGF2α were independent predictors of non-alcoholic fatty liver and a strong association of urinary 8-iso-PGF2α and of serum soluble NOX2-derived peptide with the severity of steatosis at ultrasound was also observed.

Conclusions

We demonstrated increased markers of oxidative stress in subjects with non-alcoholic fatty liver. Urinary 8-iso-PGF2α and serum soluble NOX2-derived peptide levels were independent from obesity, diabetes and metabolic syndrome and increased with the severity of liver steatosis at ultrasound.

【 授权许可】

   
2014 Del Ben et al.; licensee BioMed Central Ltd.

【 参考文献 】

• [1]Angulo P: Nonalcoholic fatty liver disease. N Engl J Med 2002, 346:1221-1231.
• [2]Bedogni G, Miglioli L, Masutti F, Tiribelli C, Marchesini G, Bellentani S: Prevalence of and risk factors for non-alcoholic fatty liver disease: the dionysos nutrition and liver study. Hepatology 2005, 42:44-52.
• [3]Angelico F, Del Ben M, Conti R, Francioso S, Feole K, Maccioni D, Antonini TM, Alessandri C: Non alcoholic fatty liver disease: an hepatic consequence of common metabolic diseases. J Gastroenterol Hepatol 2003, 18:588-594.
• [4]Kotronen A, Yki-Järvinen H: Fatty liver: a novel component of the metabolic syndrome. Arterioscler Thromb Vasc Biol 2008, 28:27-38.
• [5]Angelico F, Del Ben M, Conti R, Francioso S, Feole K, Fiorello S, Cavallo MG I, Zalunardo B, Lirussi F, Alessandri C, Violi F: Insulin resistance, the metabolic syndrome, and nonalcoholic fatty liver disease. J Clin Endocrinol Metab 2005, 90:1578-1582.
• [6]Targher G, Day CP, Bonora E: Risk of cardiovascular disease in patients with nonalcoholic fatty liver disease. N Engl J Med 2010, 363:1341-1350.
• [7]Del Ben M, Baratta F, Polimeni L, Angelico F: Non-alcoholic fatty liver disease and cardiovascular disease: epidemiological, clinical and pathophysiological evidences. Intern Emerg Med 2012, 7(Suppl 3):S291-S296.
• [8]Videla LA, Rodrigo R, Araya J, Poniachik J: Insulin resistance and oxidative stress interdependency in non-alcoholic fatty liver disease. Trends Mol Med 2006, 12:555-558.
• [9]Day CP: Pathogenesis of steatohepatitis. Best Pract Res Clin Gastroenterol 2002, 16:663-678.
• [10]Tilg H, Moschen AR: Evolution of inflammation in nonalcoholic fatty liver disease: the multiple parallel hits hypothesis. Hepatology 2010, 52:1836-1846.
• [11]Yilmaz Y: Review article: is non-alcoholic fatty liver disease a spectrum, or are steatosis and non-alcoholic steatohepatitis distinct conditions? Aliment Pharmacol Ther 2012, 36:815-823.
• [12]Sanyal AJ, Chalasani N, Kowdley KV, McCullough A, Diehl AM, Bass NM, Neuschwander-Tetri BA, Lavine JE, Tonascia J, Unalp A, Van Natta M, Clark J, Brunt EM, Kleiner DE, Hoofnagle JH, Robuck PR NASHCRN: Pioglitazone, vitamin E, or placebo for nonalcoholic steatohepatitis. New Engl J Med 2010, 362:1675-1685.
• [13]Chalasani N, Younossi Z, Lavine JE, Diehl AM, Brunt EM, Cusi K, Michael C, Arun Sanyal J: The diagnosis and management of non-alcoholic fatty liver disease: Practice Guideline by the American Association for the Study of Liver Diseases, American College of Gastroenterology, and the American Gastroenterological Association. Hepatology 2012, 55:2005-2023.
• [14]Chalasani N, Deeg MA, Crabb DW: Systemic levels of lipid peroxidation and its metabolic and dietary correlates in patients with nonalcoholic steatohepatitis. Am J Gastroenterol 2004, 99:1497-1502.
• [15]Yesilova Z, Yaman H, Oktenli C, Ozcan A, Uygun A, Cakir E, Sanisoglu SY, Erdil A, Ates Y, Aslan M, Musabak U, Erbil MK, Karaeren N, Dagalp K: Systemic markers of lipid peroxidation and antioxidants in patients with nonalcoholic fatty liver disease. Am J Gastroenterol 2005, 100:850-855.
• [16]Narasimhan S, Gokulakrishnan K, Sampathkumar R, Farooq S, Ravikumar R, Mohan V, Balasubramanyam M: Oxidative stress is independently associated with non-alcoholic fatty liver disease (NAFLD) in subjects with and without type 2 diabetes. Clin Biochem 2010, 43:815-821.
• [17]Nobili V, Parola M, Alisi A, Marra F, Piemonte F, Mombello C, Sutti S, Povero D, Maina V, Novo E, Albano E: Oxidative stress parameters in paediatric non-alcoholic fatty liver disease. Intern J Molec Med 2010, 26:471-476.
• [18]Irie M, Sohda T, Iwata K, Kunimoto H, Fukunaga A, Kuno S, Yotsumoto K, Sakurai K, Iwashita H, Hirano G, Ueda SI, Yokoyama K, Morihara D, Nishizawa S, Anan A, Takeyama Y, Sakamoto M, Shakado S, Sakisaka S: Levels of the oxidative stress marker g-glutamyltranspeptidase at different stages of nonalcoholic fatty liver disease. J Intern Med Res 2012, 40:924-933.
• [19]Pirgon O, Bilgin H, Kurku H, Cekmez F, Dündar BN: Association between insulin resistance and oxidative stress parameters in obese adolescents with non-alcoholic fatty liver disease. J Clin Res Pediatr Endocrinol 2013, 5:33-39.
• [20]Bonnefont-Rousselot D, Ratziu V, Giral P, Charlotte F, Beucler I, Poynard T: For the lido study group: blood oxidative stress markers are unreliable markers of hepatic steatosis. Alim Pharmacol Ther 2006, 23:91-99.
• [21]Il’yasova D, Scarbrough P, Spasojevic I: Urinary biomarkers of oxidative status. Clin Chim Acta 2012, 413:1446-1453.
• [22]Montuschi P, Barnes PJ, Roberts LJ: Isoprostanes: markers and mediators of oxidative stress. FASEB J 2004, 18:1791-1800.
• [23]Praticò D: Prostanoid and isoprostanoid pathways in atherogenesis. Atherosclerosis 2008, 201:8-16.
• [24]Cave AC, Brewer AC, Narayanapanicker A, Ray R, Grieve DJ, Walker S, Shah AM: NADPH oxidases in cardiovascular health and disease. Antioxid Redox Signal 2006, 8:691-728.
• [25]Cangemi R, Angelico F, Loffredo L, Del Ben M, Pignatelli P, Martini A, Violi F: Oxidative stress-mediated arterial dysfunction in patients with metabolic syndrome: effect of ascorbic acid. Free Rad Biol Med 2007, 43:853-859.
• [26]Angelico F, Loffredo L, Pignatelli P, Augelletti T, Carnevale R, Pacella A, Albanese F, Mancini I, Di Santo S, Del Ben M, Violi F: Weight loss is associated with improved endothelial dysfunction via NOX2-generated oxidative stress down-regulation in patients with the metabolic syndrome. Int Emerg Med 2012, 7:219-227.
• [27]Loffredo L, Martino F, Carnevale R, Pignatelli P, Catasca E, Perri L, Calabrese CM, Palumbo MM, Baratta F, Del Ben M, Angelico F, Violi F: Obesity and hypercholesterolemia are associated with NOX-2 generated oxidative stress and arterial dysfunction. J Pediatr 2012, 161:1004-1009.
• [28]Del Ben M, Fabiani M, Loffredo L, Polimeni L, Carnevale R, Baratta F, Brunori M, Albanese F, Augelletti T, Violi F, Angelico F: Oxidative stress mediated arterial dysfunction in patients with obstructive sleep apnoea and the effect of continuous positive airway pressure treatment. BMC Pulm Med 2012, 23(12):36.
• [29]World Health Organisation: Definition diagnosis and classification of diabetes mellitus and its complications. Geneva, Switzerland: World Health Organisation; 1999. [Report of a WHO Consultation]
• [30]Grundy SM, Cleeman JI, Daniels SR, Donato KA, Eckel RH, Franklin BA, Gordon DJ, Krauss RM, Savage PJ, Smith SC Jr, Spertus JA, Costa F, American Heart Association; National Heart, Lung, and Blood Institute: Diagnosis and management of the metabolic syndrome: an american heart association/national heart, lung, and blood institute scientific statement. Circulation 2005, 112:2735-2752.
• [31]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, 28:412-419.
• [32]Pignatelli P, Carnevale R, Cangemi R, Loffredo L, Sanguigni V, Stefanutti C, Basili S, Violi F: Atorvastatin inhibits gp91phox circulating levels in patients with hypercholesterolemia. Arterioscler Thromb Vasc Biol 2010, 30:360-367.
• [33]Wang Z, Ciabattoni G, Creminon C, Lawson J, Fitzgerald GA, Patrono C, Maclouf J: Immunological characterization of urinary 8-epi-prostaglandin F2 alpha excretion in man. J Pharmacol Exper Ther 1995, 275:94-100.
• [34]Hamaguchi M, Kojima T, Itoh Y, Harano Y, Fujii K, Nakajima T, Kato T, Takeda N, Okuda J, Ida K, Kawahito Y, Yoshikawa T, Okanoue T: The severity of ultrasound findings in nonalcoholic fatty liver disease reflects the metabolic syndrome and visceral fat accumulation. Am J Gastroenterol 2007, 102:1-8.
• [35]Seki S, Kitata T, Yamada T, Sakaguchi H, Nakatami K, Wakasa K: In situ detection of lipid peroxidation and oxidative DNA damage in non-alcoholic fatty liver diseases. J Hepatol 2002, 37:56-62.
• [36]Roest M, Voorbij HA, Van der Schouw YT, Peeters PH, Teerlink T, Scheffer PG: High levels of urinary F2-isoprostanes predict cardiovascular mortality in postmenopausal women. J Clin Lipidol 2008, 2:298-303.
• [37]Feldstein AE, Anna Wieckowska A, Rocio Lopez A, Yao-Chang L, Nizar Zein N, Arthur McCullough J, Rocio Lopez A, Yao-Chang L, Nizar N, Arthur J: Cytokeratin-18 fragment levels as noninvasive biomarkers for nonalcoholic steatohepatitis: a multicenter validation study. Hepatology 2009, 50:1072-1078.
• [38]Dasarathy S, Dasarathy J, Khiyami A, Joseph R, Lopez R, McCullough AJ: Validity of real time ultrasound in the diagnosis of hepatic steatosis: a prospective study. J Hepatol 2009, 51:1061-1067.