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High-glucose toxicity is mediated by AICAR-transformylase/IMP cyclohydrolase and mitigated by AMP-activated protein kinase in Caenorhabditis elegans.

ABSTRACT: The enzyme AICAR-transformylase/IMP cyclohydrolase (ATIC) catalyzes the last two steps of purine de novo synthesis. It metabolizes 5-aminoimidazole-4-carboxamide ribonucleoside (AICAR), which is an AMP analogue, leading to activation of AMP-activated kinase (AMPK). We investigated whether the AICAR-ATIC pathway plays a role in the high glucose (HG)-mediated DNA damage response and AICAR-mediated AMPK activation, explaining the detrimental effects of glucose on neuronal damage and shortening of the lifespan. HG up-regulated the expression and activity of the Caenorhabditis elegans homologue of ATIC, C55F2.1 (atic-1), and increased the levels of reactive oxygen species and methylglyoxal-derived advanced glycation end products. Overexpression of atic-1 decreased the lifespan and head motility and increased neuronal damage under both standard and HG conditions. Inhibition of atic-1 expression, by RNAi, under HG was associated with increased lifespan and head motility and reduced neuronal damage, reactive oxygen species, and methylglyoxal-derived advanced glycation end product accumulation. This effect was independent of an effect on DNA damage or antioxidant defense pathways, such as superoxide dismutase (sod-3) or glyoxalase-1 (glod-4), but was dependent on AMPK and accumulation of AICAR. Through AMPK, AICAR treatment also reduced the negative effects of HG. The mitochondrial inhibitor rotenone abolished the AICAR/AMPK-induced amelioration of HG effects, pointing to mitochondria as a prime target of the glucotoxic effects in C. elegans We conclude that atic-1 is involved in glucotoxic effects under HG conditions, either by blocked atic-1 expression or via AICAR and AMPK induction.

SUBMITTER: Riedinger C

PROVIDER: S-EPMC5880143 | biostudies-literature | 2018 Mar

REPOSITORIES: biostudies-literature

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High-glucose toxicity is mediated by AICAR-transformylase/IMP cyclohydrolase and mitigated by AMP-activated protein kinase in <i>Caenorhabditis elegans</i>.

Riedinger Christin C Mendler Michael M Schlotterer Andrea A Fleming Thomas T Okun Jürgen J Hammes Hans-Peter HP Herzig Stephan S Nawroth Peter P PP

The Journal of biological chemistry 20180202 13

The enzyme AICAR-transformylase/IMP cyclohydrolase (ATIC) catalyzes the last two steps of purine <i>de novo</i> synthesis. It metabolizes 5-aminoimidazole-4-carboxamide ribonucleoside (AICAR), which is an AMP analogue, leading to activation of AMP-activated kinase (AMPK). We investigated whether the AICAR-ATIC pathway plays a role in the high glucose (HG)-mediated DNA damage response and AICAR-mediated AMPK activation, explaining the detrimental effects of glucose on neuronal damage and shorteni ...[more]

PMID: 29414769

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Project description:5-Aminoimidazole-4-carboxyamide-ribonucleoside (AICAR), a prodrug activator of AMP-activated protein kinase (AMPK), increased hepatic expression of cytochrome P450 4a10, 4a14, and 4a31 mRNAs 2-, 3-, and 4-fold, respectively, and liver microsomal lauric acid ω-hydroxylation increased 2.8-fold. Likewise, mRNA levels of the peroxisome proliferator-activated receptor α (PPARα)-responsive genes, Acox1, Acadm, Cpt1a, and Fabp1, were also increased by AICAR treatment. AICAR did not elicit these changes in PPARα null mice. In isolated murine hepatocytes, AICAR and adenosine produced similar effects, and these responses were blocked by the PPARα antagonist [(2S)-2-[[(1Z)-1-methyl-3-oxo-3-[4-(trifluoromethyl)phenyl]-1-propenyl]amino]-3-[4-[2-(5-methyl-2-phenyl-4-oxazolyl)ethoxy]phenyl]propyl]-carbamic acid ethyl ester (GW6471). Inhibition of AMPK using compound C (dorsomorphin or 6-[4-(2-piperidin-1-ylethoxy)phenyl]-3-pyridin-4-ylpyrazolo[1,5-a]pyrimidine) did not block the induction of the PPARα-responsive genes by AICAR or adenosine, and 6,7-dihydro-4-hydroxy-3-(2'-hydroxy[1,1'-biphenyl]-4-yl)-6-oxo-thieno[2,3-b]pyridine-5-carbonitrile (A-769662), a non-nucleoside, direct activator of AMPK, did not increase expression of PPARα-responsive genes. An inhibitor of adenosine kinase, 5-iodotubercidin, blocked these responses, suggesting that the phosphorylation of AICAR and adenosine to AICAR 5'-monophosphate (ZMP) or AMP, respectively, was required. Concentrations of ZMP and AMP were elevated and ATP levels diminished at 24 h. The PPARα-dependent responses were associated with increased concentrations of oleic acid, a potent PPARα agonist, and diminished levels of oleoyl-CoA. Oleoyl-CoA synthase activity was inhibited by ZMP and AMP with IC(50) values of 0.28 and 0.41 mM, respectively. These results suggest that PPARα is activated by increased concentrations of free fatty acids that may arise from impaired fatty acid metabolism caused by altered levels of ATP, AMP, and ZMP after AICAR or adenosine treatment.

Dataset Information

High-glucose toxicity is mediated by AICAR-transformylase/IMP cyclohydrolase and mitigated by AMP-activated protein kinase in Caenorhabditis elegans.

Publications

High-glucose toxicity is mediated by AICAR-transformylase/IMP cyclohydrolase and mitigated by AMP-activated protein kinase in <i>Caenorhabditis elegans</i>.

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Dataset Information

High-glucose toxicity is mediated by AICAR-transformylase/IMP cyclohydrolase and mitigated by AMP-activated protein kinase in Caenorhabditis elegans.

Publications

High-glucose toxicity is mediated by AICAR-transformylase/IMP cyclohydrolase and mitigated by AMP-activated protein kinase in &lt;i&gt;Caenorhabditis elegans&lt;/i&gt;.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets

High-glucose toxicity is mediated by AICAR-transformylase/IMP cyclohydrolase and mitigated by AMP-activated protein kinase in <i>Caenorhabditis elegans</i>.