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Tetrahydrobiopterin and alkylglycerol monooxygenase substantially alter the murine macrophage lipidome.

ABSTRACT: Tetrahydrobiopterin is a cofactor synthesized from GTP with well-known roles in enzymatic nitric oxide synthesis and aromatic amino acid hydroxylation. It is used to treat mild forms of phenylketonuria. Less is known about the role of tetrahydrobiopterin in lipid metabolism, although it is essential for irreversible ether lipid cleavage by alkylglycerol monooxygenase. Here we found intracellular alkylglycerol monooxygenase activity to be an important regulator of alkylglycerol metabolism in intact murine RAW264.7 macrophage-like cells. Alkylglycerol monooxygenase was expressed and active also in primary mouse bone marrow-derived monocytes and "alternatively activated" M2 macrophages obtained by interleukin 4 treatment, but almost missing in M1 macrophages obtained by IFN-? and lipopolysaccharide treatment. The cellular lipidome of RAW264.7 was markedly changed in a parallel way by modulation of alkylglycerol monooxygenase expression and of tetrahydrobiopterin biosynthesis affecting not only various ether lipid species upstream of alkylglycerol monooxygenase but also other more complex lipids including glycosylated ceramides and cardiolipins, which have no direct connection to ether lipid pathways. Alkylglycerol monooxygenase activity manipulation modulated the IFN-?/lipopolysaccharide-induced expression of inducible nitric oxide synthase, interleukin-1?, and interleukin 1 receptor antagonist but not transforming growth factor ?1, suggesting that alkylglycerol monooxygenase activity affects IFN-?/lipopolysaccharide signaling. Our results demonstrate a central role of tetrahydrobiopterin and alkylglycerol monooxygenase in ether lipid metabolism of murine macrophages and reveal that alteration of alkylglycerol monooxygenase activity has a profound impact on the lipidome also beyond the class of ether lipids.

SUBMITTER: Watschinger K

PROVIDER: S-EPMC4345615 | biostudies-literature | 2015 Feb

REPOSITORIES: biostudies-literature

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Tetrahydrobiopterin and alkylglycerol monooxygenase substantially alter the murine macrophage lipidome.

Watschinger Katrin K Keller Markus A MA McNeill Eileen E Alam Mohammad T MT Lai Steven S Sailer Sabrina S Rauch Veronika V Patel Jyoti J Hermetter Albin A Golderer Georg G Geley Stephan S Werner-Felmayer Gabriele G Plumb Robert S RS Astarita Giuseppe G Ralser Markus M Channon Keith M KM Werner Ernst R ER

Proceedings of the National Academy of Sciences of the United States of America 20150209 8

Tetrahydrobiopterin is a cofactor synthesized from GTP with well-known roles in enzymatic nitric oxide synthesis and aromatic amino acid hydroxylation. It is used to treat mild forms of phenylketonuria. Less is known about the role of tetrahydrobiopterin in lipid metabolism, although it is essential for irreversible ether lipid cleavage by alkylglycerol monooxygenase. Here we found intracellular alkylglycerol monooxygenase activity to be an important regulator of alkylglycerol metabolism in inta ...[more]

PMID: 25675482

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Project description:Reports that low-intensity microwave radiation can induce heat-shock reporter gene expression in the nematode, Caenorhabditis elegans, have recently been reinterpreted as a subtle thermal effect caused by very slight heating. This study used a microwave exposure system (1.0 GHz, 0.5 W power input; SAR 0.9-3 mW kg-1 for 6-well plates) that minimises the temperature differential between sham and exposed conditions to ≤ 0.1°C. Comparable measurement and simulation studies of SAR distribution within this exposure system are presented. We compared 5 Affymetrix gene-arrays of pooled triplicate RNA populations from sham-exposed L4/adult worms against 5 gene-arrays of pooled RNA from microwave-exposed worms (taken from the same source population in each run). Few genes showed consistent expression changes across all 5 comparisons, and all such expression changes appeared modest after applying standard normalisation procedures (≤ 30% up- or down-regulated). The number of statistically significant differences in gene expression (846) was less than the false-positive rate expected by chance (1131). As one example, an apparent up-regulation of the vit-3 vitellogenin gene by microwave exposure was not mirrored by similar changes affecting the other co-regulated members of the same vit gene family. We conclude that the pattern of gene expression in L4/adult C elegans is not substantially perturbed by low-intensity microwave radiation, and that the minor changes observed in this study may well be explicable as false positives. As a check on the sensitivity of the Affymetrix gene-arrays used, we also compared RNA samples from N2 worms subjected to a sub-heat-shock treatment (28ºC) against controls kept at 26 ºC (but using only 2 gene arrays per condition). After similar normalisation, many more genes (3712) showed substantial expression changes (i.e. > 2-fold at p < 0.05), including a group of six heat-shock genes which were strongly but unexpectedly down-regulated (by > 10-fold). However, further replication and confirmation by real-time RT-PCR would be needed to establish how many of these changes might also be false positives. Experimenter name: Adam Dawe Experimenter phone: +27 21 959 2364 adam@sanbi.ac.za Experimenter institute: South African National Bioinformatics Institute Experimenter address: University of Western Cape, Old Chemistry Building, University of Western Cape, Modderdam Road, Bellville 7530, Capetown Experimenter zip/postal_code: 7530 Experimenter country: South Africa Keywords: Microwave radiation, gene expression, gene arrays, Caenorhabditis elegans

Dataset Information

Tetrahydrobiopterin and alkylglycerol monooxygenase substantially alter the murine macrophage lipidome.

Publications

Tetrahydrobiopterin and alkylglycerol monooxygenase substantially alter the murine macrophage lipidome.

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