GLUTAMINE-CYCLING PATHWAY IN METABOLIC SYNDROME

SILVIA SOOKOIAN; CARLOS J. PIROLA

Glutamine in Clinical Nutrition

Kings College, SPRINGER

Lugar: New York; Año: 2015; p. 255 - 275

1) The Metabolic syndrome (MS) is a cluster of strongly related intermediate phenotypes such as central obesity, glucose intolerance, dyslipidemias, hypertension and fatty liver with a common underlying metabolic derangement characterized by insulin resistance (IR). 2) The glutamine-cycling pathway participates in the pathogenesis of the MS and might be prominently involved in the development of the systemic underlying metabolic derangement. High-throughput metabolomic profiling in patients with MS showed a distinctive metabolic signature associated with branched-chain amino acids (BCCA). In fact, circulating levels of glutamic acid and other BCAA have prognostic value in the risk prediction of MS-related complications. The hyperaminoacidemia observed in patients with MS might be involved in the modulation of the insulin signaling and BCAA are potent modulators of the mTOR/p70 S6 kinase pathway. 3) The reactions of transaminations mediated by the enzymes ALT and AST regulate the levels of major Krebs cycle-intermediate metabolites and reprogram their activity according to the cellular metabolic environment. Hence, circulating levels of liver transaminases ALT and AST might be regarded as sensors of the systemic metabolic derangement occurring in patients with MS, and a change of the paradigm of ALT and AST are just markers of liver injury is proposed. Mechanisms behind the transcriptional and posttranscriptional regulation of the liver transaminasas are explored by systems biology approaches. 4) Gene variants in glutaminase 2 (GLS2) or Glutamine synthase (glutamate-ammonia ligase, GLUL) might provide a molecular explanation to connect genomic variation with enzymatic defects in patients with MS, and may explain the raise in glutamic acid levels observed in this patients suggesting a ?genotype-dependent glutamate-metabolotype?. In addition, Glutamate dehydrogenase (GLUD1), a mitochondrial matrix enzyme that catalyzes the oxidative deamination of glutamate to alpha-ketoglutarate and ammonia may have an important role in incorporating ammonia to the amino acids metabolism and regulating amino acid-induced insulin secretion because activating mutations in this gene are a common cause of congenital hyperinsulinism. 5) Glutamate might be involved in the fetal metabolic programming of the MS-related phenotypes by regulating the hypothalamic signaling cascade of appetite control. 6) Deregulation of glutamine metabolism in the liver might be involved in neoplastic transformation and might explain the high prevalence of liver cancer observed in patients with MS.