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Alanine and Aspartate Aminotransferase and Glutamine-Cycling Pathway: Their Roles in Pathogenesis of Metabolic Syndrome

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Alanine and Aspartate Aminotransferase and Glutamine-Cycling Pathway: Their Roles in Pathogenesis of Metabolic Syndrome Online Submissions: http://www.wjgnet.com/1007-9327office World J Gastroenterol 2012 August 7; 18(29): 3775-3781 [email protected] ISSN 1007-9327 (print) ISSN 2219-2840 (online) doi:10.3748/wjg.v18.i29.3775 © 2012 Baishideng. All rights reserved. FIELD OF VISION Alanine and aspartate aminotransferase and glutamine-cycling pathway: Their roles in pathogenesis of metabolic syndrome Silvia Sookoian, Carlos J Pirola Silvia Sookoian, Department of Clinical and Molecular Hepa- factors such as obesity, insulin resistance (IR), high tology, Institute of Medical Research A Lanari-IDIM, Univer- blood pressure, and dyslipidemia were associated with sity of Buenos Aires-National Council of Scientific and Tech- several metabolites, including branched-chain amino nological Research (CONICET), Ciudad Autónoma de Buenos acids, other hydrophobic amino acids, tryptophan Aires 1427, Argentina breakdown products, and nucleotide metabolites. In Carlos J Pirola, Department of Molecular Genetics and Biol- addition, the authors found a significant association of ogy of Complex Diseases, Institute of Medical Research A IR traits with glutamine, glutamate and the glutamine- Lanari-IDIM, University of Buenos Aires-National Council of Scientific and Technological Research (CONICET), Ciudad Au- to-glutamate ratio. These data provide new insight into tónoma de Buenos Aires 1427, Argentina the pathogenesis of MS-associated phenotypes and in- Author contributions: Sookoian S and Pirola CJ designed the troduce a crucial role of glutamine-cycling pathway as study, analyzed and interpreted the data, and prepared and wrote prominently involved in the development of metabolic the manuscript. risk. We consider that the hypothesis about the role of Supported by Grants PICT 2008-1521 and 2010-0441, from abnormal glutamate metabolism in the pathogenesis of Agencia Nacional de Promoción Científica y Tecnológica; and the MS is certainly challenging and suggests the criti- UBACYT CM04, from Universidad de Buenos Aires cal role of the liver in the global metabolic modulation Correspondence to: Silvia Sookoian, MD, PhD, Department as glutamate metabolism is linked with aminotrans- of Clinical and Molecular Hepatology, Institute of Medical ferase reactions. We discuss here the critical role of Research A Lanari-IDIM, University of Buenos Aires-National Council of Scientific and Technological Research (CONICET), the “liver metabolism” in the pathogenesis of the MS Instituto de Investigaciones Médicas A. Lanari. Av. Combat- and IR, and postulate that before fatty liver develops, iente de Malvinas 3150, Ciudad Autónoma de Buenos Aires abnormal levels of liver enzymes, such as alanine and 1427, Argentina. [email protected] aspartate aminotransferases might reflect high levels Telephone: +54-11-45148701 Fax: +54-11-45238947 of hepatic transamination of amino acids in the liver. Received: May 29, 2012 Revised: June 15, 2012 Accepted: June 28, 2012 © 2012 Baishideng. All rights reserved. Published online: August 7, 2012 Key words: Alanine; Aspartate; Glutamine; Glutamate; 2-oxoglutarate; Glycolysis; Pyruvate Abstract Peer reviewers: Ferruccio Bonino, MD, PhD, Professor of Although new research technologies are constantly Gastroenterology, Director of Liver and Digestive Disease Division, Department of Internal Medicine, University used to look either for genes or biomarkers in the of Pisa, Director of General Medicine 2 Unit University prediction of metabolic syndrome (MS), the patho- Hospital of Pisa, Via Roma 67, 56124 Pisa, Italy; Andrzej S genesis and pathophysiology of this complex disease Tarnawski, MD, PhD, DSc (Med), Professor of Medicine, remains a major challenge. Interestingly, Cheng et al Chief Gastroenterology, VA Long Beach Health Care System, recently investigated possible pathways underlying MS University of California, Irvine, CA, 5901 E. Seventh Str., Long by high-throughput metabolite profiling in two large Beach, CA 90822, United States and well characterized community-based cohorts. The authors explored by liquid chromatography and Sookoian S, Pirola CJ. Alanine and aspartate aminotrans- mass spectrometry the plasma concentrations of 45 ferase and glutamine-cycling pathway: Their roles in patho- distinct metabolites and examined their relation to genesis of metabolic syndrome. World J Gastroenterol 2012; cardiometabolic risk, and observed that metabolic risk 18(29): 3775-3781 Available from: URL: http://www.wjgnet. WJG|www.wjgnet.com 3775 August 7, 2012|Volume 18|Issue 29| Sookoian S et al . Alanine and aspartate aminotransferase and glutamine-cycling pathway com/1007-9327/full/v18/i29/3775.htm DOI: http://dx.doi. that individuals with metabolic risk factors have higher org/10.3748/wjg.v18.i29.3775 circulating concentrations of glutamate and BCAA, and lower concentrations of glutamine, and suggest that glu- tamate may contribute to the development of the MS. Moreover, the authors observed that circulating levels of INVITED COMMENTARY ON HOT BCAA are not only associated with obesity and impaired ARTICLES glucose tolerance but also with dyslipidemia and blood pressure. The metabolic syndrome (MS), a complex disorder as- sociated with several metabolic disturbances and mostly What can this metabolomic data tell us about the characterized by insulin resistance (IR) in several tissues, pathogenesis of MS? results from a complex interplay between genetic and en- These data open new perspectives about the patho- [1] vironmental factors . Among the environmental factors, genesis of MS-associated phenotypes and introduce a decreased physical activity, increased nutrient availability crucial role of glutamine-cycling pathway as prominently and over nutrition, play an important role and are also involved in the development of metabolic risk. largely considered to be responsible for the modern epi- Actually, the role of glutamine-cycle in the regulation demic of MS-related phenotypes, such as obesity, arterial of metabolic syndrome-related phenotypes was pos- hypertension and type 2 diabetes (T2D). Moreover, the tulated many years ago, as Hermanussen et al[8] showed pathogenesis of IR is strongly associated with the ability that chronic hyperglutamatemia may intoxicate arcuate of the liver to suppress endogenous glucose production, nucleus neurons, thereby disrupting the hypothalamic suggesting that this organ is a key player in the patho- signaling cascade of leptin action, causing hyperphagia, physiology of the MS. Some metabolic disturbances in obesity and hyperleptinaemia. Surprisingly, glutamate has the hepatic tissue, such as abnormal triglycerides accu- also been associated with metabolic programming and it mulation observed in fatty liver, have been suggested as was postulated that the thrifty phenotype, the epidemio- the trigger events and perhaps the causative factors of logical association between poor fetal and infant growth IR[2,3]. As such, nonalcoholic fatty liver disease (NAFLD) and the subsequent development of the MS, may be the is now considered to be an additional component of [8] consequence of fetal hyperglutamatemia . the MS strongly associated with cardiovascular disease [1,4-6] In addition, previous evidences from a human study, (CVD) . including a metabolic profiling performed on 74 obese Although significant efforts have been made in the and 67 lean subjects, identified a cluster of obesity-asso- last years and new research technologies are constantly ciated changes in specific amino acid, acylcarnitine, and used to look for either genes or biomarkers in the MS organic acid metabolites in obese compared to lean sub- prediction, the pathogenesis and pathophysiology of this jects that was associated with IR[9]. Newgard [9] tested complex disease remains a major challenge. et al We read with great interest the article by Cheng et al[7] the effect of supplementation of high fat diet with recently published in Circulation. Interestingly, Cheng et al[7] BCAA in an experimental study, and showed that this investigated possible pathways underlying MS by high- model was associated with decreased levels of circulating throughput metabolite profiling in two large and well α-ketoglutarate and increased levels of glutamate, and characterized community-based cohorts, including 1015 speculated that the accumulation of glutamate increases the transamination of pyruvate to alanine, leading to the individuals from the Framingham Heart Study and [9] 746 from the Malmö Diet and Cancer Study. By liquid development of obesity-associated IR. Newgard et al chromatography and mass spectrometry, the authors in fact extended this reasoning to that the increase in explored the plasma concentrations of 45 distinct me- alanine, a highly gluconeogenic amino acid, contributes tabolites and examined their relation to cardiometabolic to the development of glucose intolerance in obesity, as risk, and found that metabolic risk factors such as obe- circulating alanine levels are elevated in obese subjects. sity, IR, high blood pressure, and dyslipidemia were as- Furthermore, a recent human study exploring me- sociated with several metabolites, including branched- tabolite predictors of deteriorating glucose tolerance in chain amino acids (BCAA), other hydrophobic amino two Finnish population-based studies consisting of 1873 acids, tryptophan breakdown products, and nucleotide individuals and reexamination of 618 individuals after metabolites. In addition, the authors observed a signifi- 6.5 years in one of the cohorts showed that alterations [10] cant association
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