{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nDiacylglycerol kinases (DGKs) are enzymes that phosphorylate diacylglycerol (DAG) into phosphatidic acid (PA), thereby tightly regulating lipid signaling and membrane composition. In the nervous system, DGKε in particular shows selectivity for arachidonoyl-containing DAG, thereby influencing the enrichment of phosphoinositide species and modulating neuronal excitability and epileptogenesis. In mouse kindling models, for example, the presence of DGKε is linked to the upregulation of key enzymes such as cyclooxygenase‑2 and tyrosine hydroxylase, thereby affecting catecholamine synthesis and seizure susceptibility."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "1"}]}, {"type": "t", "text": "\n\n"}]}, {"type": "t", "text": "\n"}, {"type": "p", "children": [{"type": "t", "text": "\nBeyond its role in neural signaling, DGK isoforms also contribute to neurodegenerative and vascular pathologies. In models of Huntington’s disease, inhibition or knockdown of DGKε ameliorates mutant huntingtin toxicity, implicating its activity in neurodegeneration. Similarly, mutations in the DGKE gene — which encodes DGKε — have been associated with thrombotic microangiopathy, a condition that appears to result from defective endothelial signaling and impaired prostaglandin production. In immune cells, related DGK isoforms modulate the balance between DAG and PA to orchestrate cytoskeletal rearrangements at the immune synapse, thus affecting antigen uptake and T cell activation. In endothelial cells, loss of DGKε disrupts vascular endothelial growth factor receptor‑2 (VEGFR2) signaling cascades, further linking its dysregulation to renal injury."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "3", "end_ref": "7"}]}, {"type": "t", "text": "\n\n"}]}, {"type": "t", "text": "\n"}, {"type": "p", "children": [{"type": "t", "text": "\nDGKε also plays a critical role in metabolic regulation and adipose tissue remodeling. In skeletal muscle, its absence leads to an accumulation of distinct unsaturated and saturated DAG species that, paradoxically, may be rapidly oxidized via enhanced mitochondrial activity, thereby preserving insulin sensitivity. In adipose tissues, DGKε deficiency is linked to dynamic remodeling: early high‐fat feeding promotes visceral fat expansion and impaired glucose clearance, whereas prolonged exposure leads to the emergence of beige adipocytes with increased thermogenic capacity and improved glycemic profiles, despite concomitant brown adipocyte dysfunction. Furthermore, precise DGKε activity is maintained by structural motifs such as a zinc finger in its C1B domain and post‐translational modifications like S‑palmitoylation, which together regulate the enzyme’s stability, localization, and activity."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "8", "end_ref": "12"}]}, {"type": "t", "text": "\n"}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Walter J Lukiw, Jian-Guo Cui, Alberto E Musto, et al. 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