• 2018-07
  • 2018-10
  • 2018-11
  • 2019-04
  • 2019-05
  • 2019-06
  • 2019-07
  • Although DGK is a lipid modulating


    Although DGKγ is a lipid-modulating enzyme, the role of DGKγ in integral cell metabolism has not been reported. We found that DGKγ made a difference on cell metabolism profile in HCC cells, which may be caused partially by the downregulation of GLUT1. Glucose is a major source of energy, and decreased GLUT1 expression may indicate a decreased utilization of energy, which in turn may correlate with suppressed behavior of cancer cells. GLUT1 is overexpressed in a significant proportion of human carcinomas, including HCC [23], [36]. Actually, we found that ectopic DGKγ expression led to a series of events, such as down-regulation of GLUT1, decrease of glucose uptake, declination of lactate and ATP production, activation of AMPK, down-regulation of cyclin D1 and cyclin E, cell cycle arrest and suppression of cell growth in HCC cells. All these results were in accordance with the effects of GLUT1 inhibitor in cancer cell lines [37]. Therefore, it was reasonable to conclude that DGKγ downregulated GLUT1 and finally inhibited cell growth in HCC. In this study, we found that it was the protein level but not mRNA level declined in DGKγ-WT but not DGKγ-KD over-expressed cells, and DGK inhibitor and lysosome inhibitor could partially rescue the suppression effect, indicating DGKγ may down-regulate GLUT1 through its kinase activity and lysosome degradation to an extent. However, the mechanism of DGKγ downregulating GLUT1 is unclear. It has been reported that growth factors could increase surface GLUT1 in part by decreasing the rate of surface GLUT1 internalization and promoting recycling of intracellular GLUT1. In the absence of growth factor, GLUT1 is internalized and degraded in lysosomes [31], [38]. DGKγ has been reported locating in Golgi apparatus in adrenal gland [39], vascular endothelial cells [40] and transfected COS7 cells [41]. Ectopic DGKγ could translocate to the plasma membrane induced by phorbol ester, ATP and arachidonic GSK2292767 what in CHO-K1 cells [42] and induced by epidermal growth factor in COS7 cells [14]. Therefore, it is possible that under the stimulation of growth factor, DGKγ could translocate to the plasma membrane, regulate the signaling transduction of growth factor and inhibit GLUT1 recycling. Further study should investigate the association between the translocation of DGKγ and the recycling regulation of GLUT1.
    Introduction Bipolar disorder is a mental illness characterized by episodes of mania and depression. The lifetime prevalence of 1% is similar in males and females and previous studies of families, twins, and adopted children provide robust evidence for a major genetic contribution to risk of disease [1]. To date, various animal models for the manic phase of bipolar disorder have been established by using several drugs such as amphetamine, methylphenidate, and ouabain [2], [3], [4], [5], or genetically modified mice [6], [7]. However, the pathogenesis of bipolar disorder and/or mania remains unclear, and better characterized animal models are needed. Diacylglycerol kinase (DGK) is an enzyme that converts diacylglycerol to phosphatidic acid [8]. Because diacylglycerol and phosphatidic acid affect various molecules such as protein kinase C (PKC) isoforms, Ras-GAP, and phosphatidylinositol 5-kinases [8], [9], [10], DGK is a key molecule in regulating the intracellular signaling. Within the DGK family, DGKβ is expressed in neuronal cells and plays an important role in higher brain function [11], [12], [13], [14]. Previous studies have revealed that the splice variant at the COOH-terminus of DGKβ was related to bipolar disorder [15]. Furthermore, we developed DGKβ KO mice and found that they showed cognitive impairment [16], mania-like behavior, such as hyperactivity, reduced anxiety, and reduced depression [17], and attention-deficit behaviors [18]. We also showed that the hyperactivity of DGKβ KO mice was ameliorated after treatment with lithium, which is a mood-stabilizing drug [17]. However, haloperidol, one of the typical antipsychotic drugs, did not ameliorate the locomotor activity or anxiety levels of DGKβ KO mice [17].