Serum aminotransferases in nonalcoholic fatty liver disease are a signature of liver metabolic perturbations at the amino acid and Krebs cycle level

American Journal of Clinical Nutrition

Volumn 103, Issue 2, 2016, Pages 422-434

  Sookoian, Silvia ^a   Castaño, Gustavo O ^e   Scian, Romina ^a,b   Gianotti, Tomas Fernández ^b   Dopazo, Hernán ^c   Rohr, Cristian ^c   Gaj, Graciela ^f   Martino, Julio San ^f   Sevic, Ina ^d   Flichman, Diego ^d   Pirola, Carlos J ^b  

^a Departments of Clinical and Molecular Hepatology   (Spain)

^b Molecular Genetics and Biology of Complex Diseases   (Spain)

^c Ecología y Evolución de Buenos Aires   (Spain)

^d UNIVERSIDAD DE BUENOS AIRES   (Argentina)

^e Hospital General de Agudos Dr Abel Zubizarreta   (Argentina)

^f NONE   (Argentina)

Author keywords

Fatty liver; Gene expression; Liver injury; Metabolomics; Transaminases

Indexed keywords

2 HYDROXYGLUTARIC ACID; ALANINE AMINOTRANSFERASE; ALANINE AMINOTRANSFERASE 2; ALKALINE PHOSPHATASE; ASPARTATE AMINOTRANSFERASE ISOENZYME 1; ASPARTATE AMINOTRANSFERASE ISOENZYME 2; CYSTAMINE; CYTOKERATIN 18; GAMMA GLUTAMYLTRANSFERASE; GLUCOSE; GLUTAMIC ACID; INSULIN; LACTIC ACID; MESSENGER RNA; METHIONINE; PALMITIC ACID; UNCLASSIFIED DRUG; AMINO ACID; BIOLOGICAL MARKER; ISOENZYME;

3' UNTRANSLATED REGION; ADULT; ALANINE AMINOTRANSFERASE BLOOD LEVEL; ALKALINE PHOSPHATASE BLOOD LEVEL; AMINO ACID METABOLISM; AMINOTRANSFERASE BLOOD LEVEL; ARTICLE; ASPARTATE AMINOTRANSFERASE BLOOD LEVEL; CASE CONTROL STUDY; CELLULAR DISTRIBUTION; CITRIC ACID CYCLE; CLINICAL ARTICLE; CONTROLLED STUDY; DISEASE SEVERITY; ENZYME ACTIVITY; FATTY ACID METABOLISM; FEMALE; GAMMA GLUTAMYL TRANSFERASE BLOOD LEVEL; GENE EXPRESSION; GENE LINKAGE DISEQUILIBRIUM; GENE LOCUS; GLUCONEOGENESIS; GLUCOSE BLOOD LEVEL; GLYCOLYSIS; HUMAN; HUMAN CELL; IN VITRO STUDY; INSULIN BLOOD LEVEL; LIVER BIOPSY; LIVER FIBROSIS; LIVER METABOLISM; MALE; METABOLIC SYNDROME X; MIDDLE AGED; NEXT GENERATION SEQUENCING; NONALCOHOLIC FATTY LIVER; PROTEIN EXPRESSION; SYSTOLIC HYPERTENSION; TRANSAMINATION; UPREGULATION; UREA CYCLE; BLOOD; COHORT ANALYSIS; CROSS-SECTIONAL STUDY; ENZYME INDUCTION; FATTY LIVER; GENETICS; INSULIN RESISTANCE; LIVER; METABOLISM; PATHOLOGY; PATHOPHYSIOLOGY; SINGLE NUCLEOTIDE POLYMORPHISM; TUMOR CELL LINE;

ALANINE TRANSAMINASE; AMINO ACIDS; ASPARTATE AMINOTRANSFERASE, CYTOPLASMIC; ASPARTATE AMINOTRANSFERASE, MITOCHONDRIAL; BIOMARKERS; CASE-CONTROL STUDIES; CELL LINE, TUMOR; CITRIC ACID CYCLE; COHORT STUDIES; CROSS-SECTIONAL STUDIES; ENZYME INDUCTION; FATTY LIVER; FEMALE; GLUCONEOGENESIS; HUMANS; INSULIN RESISTANCE; ISOENZYMES; LIVER; MALE; METABOLIC SYNDROME X; MIDDLE AGED; NON-ALCOHOLIC FATTY LIVER DISEASE; POLYMORPHISM, SINGLE NUCLEOTIDE;

EID: 84956915223     PISSN: 00029165     EISSN: 19383207     Source Type: Journal    
DOI: 10.3945/ajcn.115.118695     Document Type: Article

References (39)

1. Loomba R, Sanyal AJ. The global NAFLD epidemic. Nat Rev Gastroenterol Hepatol 2013;10:686-90.
2. Stepanova M, Younossi ZM. Independent association between nonalcoholic fatty liver disease and cardiovascular disease in the US population. Clin Gastroenterol Hepatol 2012;10:646-50.
3. Bhala N, Angulo P, van der Poorten D, Lee E, Hui JM, Saracco G, Adams LA, Charatcharoenwitthaya P, Topping JH, Bugianesi E, et al. The natural history of nonalcoholic fatty liver disease with advanced fibrosis or cirrhosis: an international collaborative study. Hepatology 2011;54:1208-16.
4. Lonardo A, Sookoian S, Chonchol M, Loria P, Targher G. Cardiovascular and systemic risk in nonalcoholic fatty liver disease-atherosclerosis as a major player in the natural course of NAFLD. Curr Pharm Des 2013;19:5177-92.
5. Sookoian S, Pirola CJ. Non-alcoholic fatty liver disease is strongly associated with carotid atherosclerosis: a systematic review. J Hepatol 2008;49:600-7.
6. Sookoian S, Castano GO, Burgueno AL, Rosselli MS, Gianotti TF, MallarDi P, Martino JS, Pirola CJ. Circulating levels and hepatic expression of molecular mediators of atherosclerosis in nonalcoholic fatty liver disease. Atherosclerosis 2010;209:585-91.
7. Sookoian S, Gianotti TF, Rosselli MS, Burgueno AL, Castano GO, Pirola CJ. Liver transcriptional profile of atherosclerosis-related genes in human nonalcoholic fatty liver disease. Atherosclerosis 2011;218:378-85.
8. Targher G, Day CP, Bonora E. Risk of cardiovascular disease in patients with nonalcoholic fatty liver disease. N Engl J Med 2010;363:1341-50.
9. Bellentani S, Saccoccio G, Masutti F, Croce LS, BranDi G, Sasso F, Cristanini G, Tiribelli C. Prevalence of and risk factors for hepatic steatosis in Northern Italy. Ann Intern Med 2000;132:112-7.
10. Clark JM, Brancati FL, Diehl AM. The prevalence and etiology of elevated aminotransferase levels in the United States. Am J Gastroenterol 2003;98:960-7.
11. Mofrad P, Contos MJ, Haque M, Sargeant C, Fisher RA, Luketic VA, Sterling RK, Shiffman ML, Stravitz RT, Sanyal AJ. Clinical and histologic spectrum of nonalcoholic fatty liver disease associated with normal ALT values. Hepatology 2003;37:1286-92.
12. Brunt EM. Histopathology of non-alcoholic fatty liver disease. Clin Liver Dis 2009;13:533-44.
13. Ioannou GN, Weiss NS, Boyko EJ, Mozaffarian D, Lee SP. Elevated serum alanine aminotransferase activity and calculated risk of coronary heart disease in the United States. Hepatology 2006;43:1145-51.
14. Siddiqui MS, Sterling RK, Luketic VA, Puri P, Stravitz RT, Bouneva I, Boyett S, Fuchs M, Sargeant C, Warnick GR, et al. Association between high-normal levels of alanine aminotransferase and risk factors for atherogenesis. Gastroenterology 2013;145:1271-9.e1-3.
15. GoesslingW, Massaro JM, Vasan RS, D'Agostino RB Sr., Ellison RC, Fox CS. Aminotransferase levels and 20-year risk of metabolic syndrome, diabetes, and cardiovascular disease. Gastroenterology 2008;135:1935-44.
16. Vozarova B, Stefan N, Lindsay RS, Saremi A, Pratley RE, Bogardus C, Tataranni PA. High alanine aminotransferase is associated with decreased hepatic insulin sensitivity and predicts the development of type 2 diabetes. Diabetes 2002;51:1889-95.
17. Song HR, Yun KE, Park HS. Relation between alanine aminotransferase concentrations and visceral fat accumulation among nondiabetic overweight Korean women. Am J Clin Nutr 2008;88:16-21.
18. Sookoian S, Pirola CJ. Obstructive sleep apnea is associated with fatty liver and abnormal liver enzymes: a meta-analysis. Obes Surg 2013;23:1815-25.
19. 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.
20. Sookoian S, Pirola CJ. NAFLD. Metabolic make-up of NASH: from fat and sugar to amino acids. Nat Rev Gastroenterol Hepatol 2014;11: 205-7.
21. Xia J, Mandal R, Sinelnikov IV, Broadhurst D, Wishart DS. Metabo-Analyst 2.0-a comprehensive server for metabolomic data analysis. Nucleic Acids Res 2012;40:W127-33.
22. Sookoian S, Castano GO, Burgueno AL, Gianotti TF, Rosselli MS, Pirola CJ. A nonsynonymous gene variant in the adiponutrin gene is associated with nonalcoholic fatty liver disease severity. J Lipid Res 2009;50:2111-6.
23. Sookoian S, Pirola CJ. Liver enzymes, metabolomics and genome-wide association studies: from systems biology to the personalized medicine. World J Gastroenterol 2015;21:711-25.
24. Sookoian S, Rosselli MS, Gemma C, Burgueno AL, Fernandez GT, Castano GO, Pirola CJ. Epigenetic regulation of insulin resistance in nonalcoholic fatty liver disease: impact of liver methylation of the peroxisome proliferator-activated receptor gamma coactivator 1alpha promoter. Hepatology 2010;52:1992-2000.
25. Jadhao SB, Yang RZ, Lin Q, Hu H, Anania FA, Shuldiner AR, Gong DW. Murine alanine aminotransferase: cDNA cloning, functional expression, and differential gene regulation in mouse fatty liver. Hepatology 2004;39:1297-302. Erratum in: Hepatology 2004;40:269.
26. Liu R, Pan X, Whitington PF. Increased hepatic expression is a major determinant of serum alanine aminotransferase elevation in mice with nonalcoholic steatohepatitis. Liver Int 2009;29:337-43.
27. Salgado MC, Meton I, Anemaet IG, Baanante IV. Activating transcription factor 4 mediates up-regulation of alanine aminotransferase 2 gene expression under metabolic stress. Biochim Biophys Acta 2014; 1839:288-96.
28. Kechagias S, Ernersson A, Dahlqvist O, Lundberg P, Lindstrom T, Nystrom FH. Fast-food-based hyper-alimentation can induce rapid and profound elevation of serum alanine aminotransferase in healthy subjects. Gut 2008;57:649-54.
29. Khoo EY, Stevenson MC, Leverton E, Cross R, Eriksson JW, Poucher SM, Spendlove I, Morris PG, Macdonald IA, Mansell P, et al. Elevation of alanine transaminase and markers of liver fibrosis after a mixed meal challenge in individuals with type 2 diabetes. Dig Dis Sci 2012;57: 3017-25.
30. Sunny NE, Parks EJ, Browning JD, Burgess SC. Excessive hepatic mitochondrial TCA cycle and gluconeogenesis in humans with nonalcoholic fatty liver disease. Cell Metab 2011;14:804-10.
31. Newgard CB, An J, Bain JR, Muehlbauer MJ, Stevens RD, Lien LF, Haqq AM, Shah SH, Arlotto M, Slentz CA, et al. A branched-chain amino acid-related metabolic signature that differentiates obese and lean humans and contributes to insulin resistance. Cell Metab 2009;9: 311-26.
32. Sharma R, Kodavanti UP, Smith LL, Mehendale HM. The uptake and metabolism of cystamine and taurine by isolated perfused rat and rabbit lungs. Int J Biochem Cell Biol 1995;27:655-64.
33. Du SX, Jin HF, Bu DF, Zhao X, Geng B, Tang CS, Du JB. Endogenously generated sulfur dioxide and its vasorelaxant effect in rats. Acta Pharmacol Sin 2008;29:923-30.
34. Zhao X, Zhang LK, Zhang CY, Zeng XJ, Yan H, Jin HF, Tang CS, Du JB. Regulatory effect of hydrogen sulfide on vascular collagen content in spontaneously hypertensive rats. Hypertens Res 2008;31:1619-30.
35. Sun Y, Tian Y, Prabha M, Liu D, Chen S, Zhang R, Liu X, Tang C, Tang X, Jin H, et al. Effects of sulfur dioxide on hypoxic pulmonary vascular structural remodeling. Lab Invest 2010;90:68-82.
36. Kathiresan S, Manning AK, Demissie S, D'Agostino RB, Surti A, Guiducci C, Gianniny L, Burtt NP, Melander O, Orho-Melander M, et al. A genome-wide association study for blood lipid phenotypes in the Framingham Heart Study. BMC Med Genet 2007;8(Suppl 1):S17.
37. Newton-Cheh C, Eijgelsheim M, Rice KM, de Bakker PI, Yin X, Estrada K, Bis JC, Marciante K, Rivadeneira F, Noseworthy PA, et al. Common variants at ten loci influence QT interval duration in the QTGEN Study. Nat Genet 2009;41:399-406.
38. Maximos M, Bril F, Portillo SP, Lomonaco R, Orsak B, Biernacki D, Suman A, Weber M, Cusi K. The role of liver fat and insulin resistance as determinants of plasma aminotransferase elevation in nonalcoholic fatty liver disease. Hepatology 2015;61:153-60.
39. Porter SA, Pedley A, Massaro JM, Vasan RS, Hoffmann U, Fox CS. Aminotransferase levels are associated with cardiometabolic risk above and beyond visceral fat and insulin resistance: the Framingham Heart Study. Arterioscler Thromb Vasc Biol 2013;33:139-46.