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  • DGK negatively regulated the extension

    2019-07-22

    DGKδ negatively regulated the extension of long axon/neurite (Fig. 4, Fig. 5, Fig. 6). The results strongly suggest that deficiency of DGKδ induces OCD-like behavior by enhancing axon/neurite outgrowth. DGKδ positively regulates growth factor signaling (Crotty et al., 2006). Therefore, DGKδ deficiency may disturb the growth-differentiation balance and enhance differentiation in neuronal cells. As described above, the SSRI, fluoxetine, attenuated the phenotypes in the DGKδ-deficient mice. Moreover, DGKδ is highly expressed in the CNQX for (Usuki et al., 2015), in which OCD-related serotonin transporter is also abundant (Matsumoto et al., 2010). Therefore, it is possible that the serotonergic system is involved in the phenotypes observed in the DGKδ-deficient mice. Physiological responses in serotonin nerve terminals are known to be influenced by changes in protein kinase C activity, which is inhibited by SSRI (Kramer et al., 1998). Because protein kinase C is activated by DG (Nishizuka, 1992), DGKδ may affect the serotonergic system through consumption of DG. However, the molecular mechanisms causing the enhanced axon/neurite extension and the OCD-like abnormal behaviors are still unclear. Further investigations are needed to reveal the mechanisms. Investigations using KO mice have already suggested that DGKβ (Kakefuda et al., 2010), ε (Rodriguez De Turco et al., 2001) and η (Isozaki et al., 2016) are involved in bipolar disorder, seizure and bipolar disorder, respectively. In the present study, we added DGKδ to the list of psychiatry-related DGK isozymes. Because OCD is probably a heterogeneous and an etiologically complex disorder, the use of different models may allow investigation of the various aspects and subtypes of OCD. In the present study, we demonstrated that brain-specific DGKδ-KO mice showed OCD-like behaviors. Therefore, the mouse can be a useful OCD model.
    Materials and methods
    Conflicts of interest
    Acknowledgments This work received support from MEXT/JSPS KAKENHI Grant Numbers 22370047 (Grant-in-Aid for Scientific Research (B)), 23116505 (Grant-in-Aid for Scientific Research on Innovative Areas), 25116704 (Grant-in-Aid for Scientific Research on Innovative Areas), 26291017 (Grant-in-Aid for Scientific Research (B)) and 15K14470 (Grant-in-Aid for Challenging Exploratory Research); the Japan Science and Technology Agency (AS221Z00794F, AS231Z00139G, and AS251Z01788Q); the Naito Foundation; the Hamaguchi Foundation for the Advancement of Biochemistry; the Daiichi-Sankyo Foundation of Life Science; the Terumo Life Science Foundation, the Futaba Electronic Memorial Foundation; the Daiwa Securities Health Foundation, the Ono Medical Research Foundation; the Japan Foundation for Applied Enzymology, the Food Science Institute Foundation; the Skylark Food Science Institute; and Asahi Group Foundation (FS).
    Introduction We observed a marked increase in the incorporation of glycerol into various lipids in cells lacking diacylglycerol kinase-ε (DGKε) compared with matched wild-type cells [1]. This increased incorporation of glycerol occurred equally for many lipids [1]. The present study was undertaken to evaluate how DGKε-deficiency impacts on glycerol metabolism. In the present work, we demonstrate that increased glycerol incorporation results from increased glycerol kinase (GK) expression. The uptake of glycerol by cells is not limited by transport across the plasma membrane, but rather by its rate of entrapment within the cell by phosphorylation by GK [2]. The expression of GK is regulated by the transcription factor p53 [3]. We also show that p53 expression is also increased in the absence of DGKε. The p53 tumor suppressor has been suggested to play a role in various metabolic processes, such as glycolysis, gluconeogenesis, and fatty acid metabolism [3], [4]. Specifically, p53 was shown to repress metabolic pathways that support tumorigenesis, such as glycolysis and the pentose phosphate pathway, and enhance pathways that are considered anti-tumorigenic, such as fatty acid oxidation [3]. Moreover, p53 appears to regulate glucose export, by increasing expression of gluconeogenic-related genes [3], [5]. Glucose export may act as a regulatory mechanism, as it prevents its use in pro-cancerous pathways, such as the pentose phosphate pathway and glycolysis [3].