Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:6.4.1.2 (acetyl-CoA carboxylase)
 2,876 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Indoleamine 2,3-dioxygenase (IDO) is expressed in antigen-presenting cells and exerts immunosuppressive effects on CD4(+) T cells. One mechanism is through the inhibition of aerobic glycolysis. Another prerequisite for T-cell proliferation and differentiation into effector cells is increased fatty acid (FA) synthesis. The effect of IDO on enzymes involved in FA synthesis was evaluated in primary human cells both in mixed lymphocyte reactions in the presence or not of the IDO inhibitor 1-dl-methyl-tryptophan, and in stimulated CD4(+) T cells in the presence or not of the general control non-derepressible 2 (GCN2) kinase activator tryptophanol (TRP). IDO or TRP inhibited cell proliferation. By assessing the level of GCN2 kinase or mammalian target of rapamycin complex 1 substrates along with a kynurenine free system we showed that IDO exerts its effect mainly through activation of GCN2 kinase. IDO or TRP down-regulated ATP-citrate lyase and acetyl coenzyme A carboxylase 1, key enzymes involved in FA synthesis. Also, IDO or TRP altered the expression of enzymes that control the availability of carbon atoms for FA synthesis, such as lactate dehydrogenase-A, pyruvate dehydrogenase, glutaminase 1 and glutaminase 2, in a way that inhibits FA synthesis. In conclusion, IDO through GCN2 kinase activation inhibits CD4(+) T-cell proliferation and down-regulates key enzymes that directly or indirectly promote FA synthesis, a prerequisite for CD4(+) T-cell proliferation and differentiation into effector cell lineages.
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PMID:Indoleamine 2,3-dioxygenase depletes tryptophan, activates general control non-derepressible 2 kinase and down-regulates key enzymes involved in fatty acid synthesis in primary human CD4+ T cells. 2614 66

Background and Purpose- Cerebral ischemic stroke elicits profound responses of CD4+ T cells, which in turn significantly affect the ischemic brain injury. ACC1 (acetyl coenzyme A carboxylase 1) is a key enzyme that has been recently found to propagate CD4+ T cell-associated inflammation by mediating de novo fatty acid synthesis; however, its role in the context of ischemic stroke remains unknown. Methods- Focal cerebral ischemia was induced by transient middle cerebral artery occlusion for 60 minutes in mice. Seahorse XF glycolysis assay and targeted lipidomic profiling were used to detect metabolic changes in CD4+ T cell after stroke. CD4 cre mice were crossed with ACC1 fl/fl mice to generate the CD4+ T-cell-specific deletion of ACC1 (CD4 creACC1 fl/fl mice) mice. Pretreatment with calorie restriction (CR; with 30% reduction of food for 4 weeks before middle cerebral artery occlusion) or post-treatment with ACC1 inhibitor, soraphen A were both used to test the effect of ACC1 modulation on poststroke neuroinflammation. Results- Cerebral ischemic stroke increased glycolysis and fatty acid synthesis in peripheral CD4+ T cells, in which the expression of ACC1 was also upregulated. CR downregulated the expression of ACC1 in CD4+ T cells after stroke. Both CD4 creACC1 fl/fl mice and CR-pretreated mice exhibited significantly reduced ischemic brain injury and preserved the balance of peripheral regulatory T cells/T helper 17 (Th17) cells. Furthermore, conditional knockout of ACC1 in CD4+ T cells attenuated the protection exerted by CR both on ischemic brain injury and peripheral balance of regulatory T cells/Th17 cells. Pharmacological inhibition of ACC1 after middle cerebral artery occlusion attenuates neuroinflammation, preserves regulatory T cells/Th17 balance, and improves neurological outcomes after ischemic stroke. Conclusions- ACC1 is a novel immune metabolic modulation target to balance the regulatory T cells and Th17 cells and blunt neuroinflammation after stroke. Inhibition of ACC1 can be a previously unrecognized mechanism that underlies CR-afforded neuroprotection against cerebral ischemic stroke.
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PMID:ACC1 (Acetyl Coenzyme A Carboxylase 1) Is a Potential Immune Modulatory Target of Cerebral Ischemic Stroke. 3117 75