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Alanine and aspartate aminotransferase and glutamine-cycling pathway: their roles in pathogenesis of metabolic syndrome.

ABSTRACT: Although new research technologies are constantly used to look either for genes or biomarkers in the prediction of metabolic syndrome (MS), the pathogenesis and pathophysiology of this complex disease remains a major challenge. Interestingly, Cheng et al recently investigated possible pathways underlying MS by high-throughput metabolite profiling in two large and well characterized community-based cohorts. The authors explored by liquid chromatography and mass spectrometry the plasma concentrations of 45 distinct metabolites and examined their relation to cardiometabolic risk, and observed that metabolic risk factors such as obesity, insulin resistance (IR), high blood pressure, and dyslipidemia were associated with several metabolites, including branched-chain amino acids, other hydrophobic amino acids, tryptophan breakdown products, and nucleotide metabolites. In addition, the authors found a significant association of IR traits with glutamine, glutamate and the glutamine-to-glutamate ratio. These data provide new insight into the pathogenesis of MS-associated phenotypes and introduce a crucial role of glutamine-cycling pathway as prominently involved in the development of metabolic risk. We consider that the hypothesis about the role of abnormal glutamate metabolism in the pathogenesis of the MS is certainly challenging and suggests the critical role of the liver in the global metabolic modulation as glutamate metabolism is linked with aminotransferase reactions. We discuss here the critical role of the "liver metabolism" in the pathogenesis of the MS and IR, and postulate that before fatty liver develops, abnormal levels of liver enzymes, such as alanine and aspartate aminotransferases might reflect high levels of hepatic transamination of amino acids in the liver.

SUBMITTER: Sookoian S

PROVIDER: S-EPMC3413046 | biostudies-literature | 2012 Aug

REPOSITORIES: biostudies-literature

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Alanine and aspartate aminotransferase and glutamine-cycling pathway: their roles in pathogenesis of metabolic syndrome.

Sookoian Silvia S Pirola Carlos J CJ

World journal of gastroenterology 20120801 29

Although new research technologies are constantly used to look either for genes or biomarkers in the prediction of metabolic syndrome (MS), the pathogenesis and pathophysiology of this complex disease remains a major challenge. Interestingly, Cheng et al recently investigated possible pathways underlying MS by high-throughput metabolite profiling in two large and well characterized community-based cohorts. The authors explored by liquid chromatography and mass spectrometry the plasma concentrati ...[more]

PMID: 22876026

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Project description:Experiments were conducted with intact rat hepatocytes to identify inhibitors and incubation conditions that cause selective inhibition of alanine aminotransferase or aspartate aminotransferase. Satisfactory results were obtained by preincubating cells with L-cycloserine or L-2-amino-4-methoxy-trans-but-3-enoic acid in the absence of added substrates. When cells were incubated for 20 min with 50 microM-L-cycloserine, alanine aminotransferase activity was decreased by 90%, whereas aspartate aminotransferase was inhibited by 10% or less. On subsequent incubation, synthesis of glucose and urea from alanine was strongly inhibited, but glucose synthesis from lactate was unaffected. L-2-Amino-4-methoxy-trans-but-3-enoic acid (400 microM) in hepatocyte incubations caused 90-95% inactivation of aspartate aminotransferase, but only 15-30% loss of alanine aminotransferase activity. After preincubation with the inhibitor, glucose synthesis from lactate was almost completely blocked; with alanine as the substrate, gluconeogenesis was unaffected, and urea synthesis was only slightly decreased. By comparison with preincubation with inhibitors, simultaneous addition of substrates (alanine; lactate plus lysine) and inhibitors (cycloserine; aminomethoxybutenoic acid) resulted in smaller decreases in aminotransferase activities and in metabolic rates. Other compounds were less satisfactory as selective inhibitors. Ethylhydrazinoacetate inactivated the two aminotransferases to similar extents. Vinylglycine was almost equally effective in blocking the two enzymes in vitro, but was a very weak inhibitor when used with intact cells. Concentrations of DL-propargylglycine (4 mM) required to cause at least 90% inhibition of alanine aminotransferase in hepatocytes also caused a 16% decrease in aspartate aminotransferase. When tested in vitro, alanine aminotransferase was, as previously reported by others, more sensitive to inhibition by amino-oxyacetate than was aspartate aminotransferase, but in liver cell incubations the latter enzyme was more rapidly inactivated by amino-oxyacetate.

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Alanine and aspartate aminotransferase and glutamine-cycling pathway: their roles in pathogenesis of metabolic syndrome.

Publications

Alanine and aspartate aminotransferase and glutamine-cycling pathway: their roles in pathogenesis of metabolic syndrome.

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