The acute regulation of hepatic ureagenesis under normal and pathologic states has been the subject of extensive investigation and numerous controversies. Recently, we have discovered that agmatine, the product of arginine metabolism via the arginine decarboxylase (ADC) reaction, stimulates fatty acid oxidation (FAO), and thus synthesis of N-acetylglutamate (NAG), an activator of carbamoyl phosphate synthetase-I (CPS-I). In addition, agmatine elevates NAG levels and urea synthesis in livers obtained from the transgenic mouse model of infant hyperinsulinism/hyperammonemia (HI/HA) syndrome. Thus, agmatine might prove a valuable therapeutic adjunct in the case of HI/HA. Therefore, the overall aims of the current renewal proposal are: (i) To elucidate the mechanism(s) by which agmatine regulates FAO, NAG and urea synthesis; and (ii) To scrutinize the mechanism(s) by which congenital HI impairs hepatic ureagenesis and leads to HA. The information sought in these aims may advance the potential application of agmatine in the treatment of impaired ureagenesis. Based on our findings we propose to explore two main hypotheses: (i) The stimulation of FAO by agmatine, triggers a metabolic cascade that leads to an increased availability of acetyl-CoA and glutamate for the synthesis of NAG, thus resulting in the activation of CPS-I; and (ii) The increased uncontrolled release of insulin by beta-cells in HI/HA patients leads to decreased FAO. A decrease in FAO, together with increased hepatic glutamate oxidation, resulting from the GDH-linked gain-of-function mutation, leads to the depletion of acetyI-CoA and glutamate and thus, diminished NAG and urea synthesis. Agmatine, however, will reverse this metabolic cascade by stimulating FAO and increasing NAG synthesis. We will use wild type and transgenic mice expressing the glutamate dehydrogenase (GDH) gain-of-function mutation in pancreatic beta-cells or the liver as a model of human HI/HA. In conjunction, we will use state-of-the-art methodologies, including 15N and/or 13C labeled precursors, Gas Chromatography-Mass Spectrometry (GC-MS) and Nuclear Magnetic Resonance (NMR), to determine the beneficial effect of agmatine on hepatic NAG and ureagenesis in this mouse model of HI/HA. The proposed studies are of clinical as well as scientific significance. The data to be generated may have tremendous clinical impact by advancing the development of a protocol to ameliorate impaired urea synthesis.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK053761-08
Application #
7192468
Study Section
Nutrition Study Section (NTN)
Program Officer
Laughlin, Maren R
Project Start
1999-04-01
Project End
2009-02-28
Budget Start
2007-03-01
Budget End
2008-02-29
Support Year
8
Fiscal Year
2007
Total Cost
$356,279
Indirect Cost
Name
Children's Hospital of Philadelphia
Department
Type
DUNS #
073757627
City
Philadelphia
State
PA
Country
United States
Zip Code
19104
Raju, Karthik; Doulias, Paschalis-Thomas; Evans, Perry et al. (2015) Regulation of brain glutamate metabolism by nitric oxide and S-nitrosylation. Sci Signal 8:ra68
Li, Bo; Qiu, Bo; Lee, David S M et al. (2014) Fructose-1,6-bisphosphatase opposes renal carcinoma progression. Nature 513:251-5
Nissim, Itzhak; Horyn, Oksana; Daikhin, Yevgeny et al. (2014) The molecular and metabolic influence of long term agmatine consumption. J Biol Chem 289:9710-29
Li, Changhong; Liu, Chengyang; Nissim, Itzhak et al. (2013) Regulation of glucagon secretion in normal and diabetic human islets by ?-hydroxybutyrate and glycine. J Biol Chem 288:3938-51
Cang, Chunlei; Zhou, Yandong; Navarro, Betsy et al. (2013) mTOR regulates lysosomal ATP-sensitive two-pore Na(+) channels to adapt to metabolic state. Cell 152:778-790
Nissim, Itzhak; Horyn, Oksana; Nissim, Ilana et al. (2012) Effects of a glucokinase activator on hepatic intermediary metabolism: study with 13C-isotopomer-based metabolomics. Biochem J 444:537-51
Falk, Marni J; Polyak, Erzsebet; Zhang, Zhe et al. (2011) Probucol ameliorates renal and metabolic sequelae of primary CoQ deficiency in Pdss2 mutant mice. EMBO Mol Med 3:410-27
Nissim, Itzhak; Horyn, Oksana; Nissim, Ilana et al. (2011) Down-regulation of hepatic urea synthesis by oxypurines: xanthine and uric acid inhibit N-acetylglutamate synthase. J Biol Chem 286:22055-68
Li, Changhong; Chen, Pan; Palladino, Andrew et al. (2010) Mechanism of hyperinsulinism in short-chain 3-hydroxyacyl-CoA dehydrogenase deficiency involves activation of glutamate dehydrogenase. J Biol Chem 285:31806-18
Cole, Jeffrey T; Mitala, Christina M; Kundu, Suhali et al. (2010) Dietary branched chain amino acids ameliorate injury-induced cognitive impairment. Proc Natl Acad Sci U S A 107:366-71

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