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Cell Metabolism Jan 2023sn-1,2-diacylglycerol (sn-1,2-DAG)-mediated activation of protein kinase Cε (PKCε) is a key pathway that is responsible for obesity-related lipid metabolism disorders,...
sn-1,2-diacylglycerol (sn-1,2-DAG)-mediated activation of protein kinase Cε (PKCε) is a key pathway that is responsible for obesity-related lipid metabolism disorders, which induces hepatic insulin resistance and type 2 diabetes. No small molecules have been previously reported to ameliorate these diseases through this pathway. Here, we screened and identified the phytochemical atractylenolide II (AT II) that reduces the hepatic sn-1,2-DAG levels, deactivates PKCε activity, and improves obesity-induced hyperlipidemia, hepatosteatosis, and insulin resistance. Furthermore, using the ABPP strategy, the diacylglycerol kinase family member DGKQ was identified as a direct target of AT II. AT II may act on a novel drug-binding pocket in the CRD and PH domains of DGKQ to thereby allosterically regulate its kinase activity. Moreover, AT II also increases weight loss by activating DGKQ-AMPK-PGC1α-UCP-1 signaling in adipose tissue. These findings suggest that AT II is a promising lead compound to improve obesity-induced insulin resistance.
Topics: Humans; Protein Kinase C-epsilon; Insulin Resistance; Diabetes Mellitus, Type 2; Diglycerides; Obesity
PubMed: 36525963
DOI: 10.1016/j.cmet.2022.11.012 -
Frontiers in Immunology 2022Activation of T cell receptor (TCR) signaling is critical for clonal expansion of CD8+ T cells. However, the effects of augmenting TCR signaling during chronic antigen...
INTRODUCTION
Activation of T cell receptor (TCR) signaling is critical for clonal expansion of CD8+ T cells. However, the effects of augmenting TCR signaling during chronic antigen exposure is less understood. Here, we investigated the role of diacylglycerol (DAG)-mediated signaling downstream of the TCR during chronic lymphocytic choriomeningitis virus clone 13 (LCMV CL13) infection by blocking DAG kinase zeta (DGKζ), a negative regulator of DAG.
METHODS
We examined the activation, survival, expansion, and phenotype of virus-specific T cell in the acute and chronic phases of LCMV CL13-infected in mice after DGKζ blockade or selective activation of ERK.
RESULTS
Upon LCMV CL13 infection, DGKζ deficiency promoted early short-lived effector cell (SLEC) differentiation of LCMV-specific CD8+ T cells, but this was followed by abrupt cell death. Short-term inhibition of DGKζ with ASP1570, a DGKζ-selective pharmacological inhibitor, augmented CD8+ T cell activation without causing cell death, which reduced virus titers both in the acute and chronic phases of LCMV CL13 infection. Unexpectedly, the selective enhancement of ERK, one key signaling pathway downstream of DAG, lowered viral titers and promoted expansion, survival, and a memory phenotype of LCMV-specific CD8+ T cells in the acute phase with fewer exhausted T cells in the chronic phase. The difference seen between DGKζ deficiency and selective ERK enhancement could be potentially explained by the activation of the AKT/mTOR pathway by DGKζ deficiency, since the mTOR inhibitor rapamycin rescued the abrupt cell death seen in virus-specific DGKζ KO CD8+ T cells.
DISCUSSION
Thus, while ERK is downstream of DAG signaling, the two pathways lead to distinct outcomes in the context of chronic CD8+ T cell activation, whereby DAG promotes SLEC differentiation and ERK promotes a memory phenotype.
Topics: Animals; Mice; CD8-Positive T-Lymphocytes; Diglycerides; Lymphocytic Choriomeningitis; Lymphocytic choriomeningitis virus; Receptors, Antigen, T-Cell; Signal Transduction; TOR Serine-Threonine Kinases; MAP Kinase Signaling System
PubMed: 36846018
DOI: 10.3389/fimmu.2022.1032113 -
International Journal of Molecular... Jul 2020An increasing number of reports suggests a significant involvement of the phosphoinositide (PI) cycle in cancer development and progression. Diacylglycerol kinases... (Review)
Review
An increasing number of reports suggests a significant involvement of the phosphoinositide (PI) cycle in cancer development and progression. Diacylglycerol kinases (DGKs) are very active in the PI cycle. They are a family of ten members that convert diacylglycerol (DAG) into phosphatidic acid (PA), two-second messengers with versatile cellular functions. Notably, some DGK isoforms, such as DGKα, have been reported to possess promising therapeutic potential in cancer therapy. However, further studies are needed in order to better comprehend their involvement in cancer. In this review, we highlight that DGKs are an essential component of the PI cycle that localize within several subcellular compartments, including the nucleus and plasma membrane, together with their PI substrates and that they are involved in mediating major cancer cell mechanisms such as growth and metastasis. DGKs control cancer cell survival, proliferation, and angiogenesis by regulating Akt/mTOR and MAPK/ERK pathways. In addition, some DGKs control cancer cell migration by regulating the activities of the Rho GTPases Rac1 and RhoA.
Topics: Animals; Cell Movement; Diacylglycerol Kinase; Diglycerides; Humans; MAP Kinase Signaling System; Neoplasm Proteins; Neoplasms
PubMed: 32722576
DOI: 10.3390/ijms21155297 -
Biochimica Et Biophysica Acta.... Jan 2020In yeast and higher eukaryotes, phospholipids and triacylglycerol are derived from phosphatidate at the nuclear/endoplasmic reticulum membrane. In de novo biosynthetic... (Review)
Review
In yeast and higher eukaryotes, phospholipids and triacylglycerol are derived from phosphatidate at the nuclear/endoplasmic reticulum membrane. In de novo biosynthetic pathways, phosphatidate is channeled into membrane phospholipids via its conversion to CDP-diacylglycerol. Its dephosphorylation to diacylglycerol is required for the synthesis of triacylglycerol as well as for the synthesis of phosphatidylcholine and phosphatidylethanolamine via the Kennedy pathway. In addition to the role of phosphatidate as a precursor, it is a regulatory molecule in the transcriptional control of phospholipid synthesis genes via the Henry regulatory circuit. Pah1 phosphatidate phosphatase and Dgk1 diacylglycerol kinase are key players that function counteractively in the control of the phosphatidate level at the nuclear/endoplasmic reticulum membrane. Loss of Pah1 phosphatidate phosphatase activity not only affects triacylglycerol synthesis but also disturbs the balance of the phosphatidate level, resulting in the alteration of lipid synthesis and related cellular defects. The pah1Δ phenotypes requiring Dgk1 diacylglycerol kinase exemplify the importance of the phosphatidate level in the misregulation of cellular processes. The catalytic function of Pah1 requires its translocation from the cytoplasm to the nuclear/endoplasmic reticulum membrane, which is regulated through its phosphorylation in the cytoplasm by multiple protein kinases as well as through its dephosphorylation by the membrane-associated Nem1-Spo7 protein phosphatase complex. This article is part of a Special Issue entitled Endoplasmic reticulum platforms for lipid dynamics edited by Shamshad Cockcroft and Christopher Stefan.
Topics: Animals; Diacylglycerol Kinase; Diglycerides; Endoplasmic Reticulum; Humans; Lipogenesis; Nuclear Envelope; Phosphatidate Phosphatase; Phospholipids; Triglycerides
PubMed: 30910690
DOI: 10.1016/j.bbalip.2019.03.006 -
Ultrasonics Sonochemistry May 2023The study aimed to evaluate the effect of ultrasonic pretreatment on the transesterification of lard with glycerol monolaurate (GML) using Lipozyme TL IM to synthesize... (Review)
Review
The study aimed to evaluate the effect of ultrasonic pretreatment on the transesterification of lard with glycerol monolaurate (GML) using Lipozyme TL IM to synthesize diacylglycerol (DAG), and the physicochemical properties of lard, GML, ultrasonic-treated diacylglycerol (named U-DAG), purified ultrasonic-treated diacylglycerol obtained by molecular distillation (named P-U-DAG), and without ultrasonic-treated diacylglycerol (named N-U-DAG) were analyzed. The optimized ultrasonic pretreatment conditions were: lard to GML mole ratio 3:1, enzyme dosage 6 %, ultrasonic temperature 80 °C, time 9 min, power 315 W. After ultrasonic pretreatment, the mixtures reacted for 4 h in a water bath at 60 °C, the content of DAG reached 40.59 %. No significant variations were observed between U-DAG and N-U-DAG in fatty acids compositions and iodine value, while P-U-DAG had lower unsaturated fatty acids than U-DAG. Differential scanning calorimetry analysis showed that the melting and crystallization properties of DAGs prepared by ultrasonic pretreatment significantly differed from lard. FTIR spectra noted transesterification reaction from lard and GML with and without ultrasonic pretreatment would not change the structure of lard. However, thermogravimetric analysis proved that N-U-DAG, U-DAG, and P-U-DAG had lower oxidation stability than lard. The higher the content of DAG, the faster the oxidation speed.
Topics: Diglycerides; Dietary Fats; Catalysis; Glycerol
PubMed: 36898248
DOI: 10.1016/j.ultsonch.2023.106354 -
Advances in Biological Regulation Jan 2019Lipid kinases regulate a wide variety of cellular functions and have emerged as one the most promising targets for drug design. Diacylglycerol kinases (DGKs) are a... (Review)
Review
Lipid kinases regulate a wide variety of cellular functions and have emerged as one the most promising targets for drug design. Diacylglycerol kinases (DGKs) are a family of enzymes that catalyze the ATP-dependent phosphorylation of diacylglycerol (DAG) to phosphatidic acid (PtdOH). Despite the critical role in lipid biosynthesis, both DAG and PtdOH have been shown as bioactive lipids mediating a number of signaling pathways. Although there is increasing recognition of their role in signaling systems, our understanding of the key enzyme which regulate the balance of these two lipid messages remain limited. Solved structures provide a wealth of information for understanding the function and regulation of these enzymes. Solving the structures of mammalian DGKs by traditional NMR and X-ray crystallography approaches have been challenging and so far, there are still no three-dimensional structures of these DGKs. Despite this, some insights may be gained by examining the similarities and differences between prokaryotic DGKs and other mammalian lipid kinases. This review focuses on summarizing and comparing the structure of prokaryotic and mammalian DGKs as well as two other lipid kinases: sphingosine kinase and phosphatidylinositol-3-kinase. How these known lipid kinases structures relate to mammalian DGKs will also be discussed.
Topics: Animals; Crystallography, X-Ray; Diacylglycerol Kinase; Diglycerides; Humans; Phosphatidic Acids; Phosphorylation; Protein Domains; Signal Transduction
PubMed: 30348515
DOI: 10.1016/j.jbior.2018.09.014 -
American Journal of Physiology. Cell... Oct 2022Mechanosensitive cation channels and Ca influx through these channels play an important role in the regulation of endothelial cell functions. Transient receptor...
Mechanosensitive cation channels and Ca influx through these channels play an important role in the regulation of endothelial cell functions. Transient receptor potential canonical channel 6 (TRPC6) is a diacylglycerol-sensitive nonselective cation channel that forms receptor-operated Ca channels in a variety of cell types. Piezo1 is a mechanosensitive cation channel activated by membrane stretch and shear stress in lung endothelial cells. In this study, we report that TRPC6 and Piezo1 channels both contribute to membrane stretch-mediated cation currents and Ca influx or increase in cytosolic-free Ca concentration ([Ca]) in human pulmonary arterial endothelial cells (PAECs). The membrane stretch-mediated cation currents and increase in [Ca] in human PAECs were significantly decreased by GsMTX4, a blocker of Piezo1 channels, and by BI-749327, a selective blocker of TRPC6 channels. Extracellular application of 1-oleoyl-2-acetyl--glycerol (OAG), a membrane permeable analog of diacylglycerol, rapidly induced whole cell cation currents and increased [Ca] in human PAECs and human embryonic kidney (HEK)-cells transiently transfected with the human gene. Furthermore, membrane stretch with hypo-osmotic or hypotonic solution enhances the cation currents in -transfected HEK cells. In HEK cells transfected with the gene, however, OAG had little effect on the cation currents, but membrane stretch significantly enhanced the cation currents. These data indicate that, while both TRPC6 and Piezo1 are involved in generating mechanosensitive cation currents and increases in [Ca] in human PAECs undergoing mechanical stimulation, only TRPC6 (but not Piezo1) is sensitive to the second messenger diacylglycerol. Selective blockers of these channels may help develop novel therapies for mechanotransduction-associated pulmonary vascular remodeling in patients with pulmonary arterial hypertension.
Topics: Calcium; Cations; Diglycerides; Endothelial Cells; Humans; Hypotonic Solutions; Ion Channels; Mechanoreceptors; Mechanotransduction, Cellular; Pulmonary Artery; TRPC6 Cation Channel
PubMed: 35968892
DOI: 10.1152/ajpcell.00313.2022 -
Trends in Pharmacological Sciences Jul 2017Although ample evidence links hepatic lipid accumulation with hepatic insulin resistance, the mechanistic basis of this association is incompletely understood and... (Review)
Review
Although ample evidence links hepatic lipid accumulation with hepatic insulin resistance, the mechanistic basis of this association is incompletely understood and controversial. Diacylglycerols (DAGs) and ceramides have emerged as the two best-studied putative mediators of lipid-induced hepatic insulin resistance. Both lipids were first associated with insulin resistance in skeletal muscle and were subsequently hypothesized to mediate insulin resistance in the liver. However, the putative roles for DAGs and ceramides in hepatic insulin resistance have proved more complex than originally imagined, with various genetic and pharmacologic manipulations yielding a vast and occasionally contradictory trove of data to sort. In this review we examine the state of this field, turning a critical eye toward both DAGs and ceramides as putative mediators of lipid-induced hepatic insulin resistance.
Topics: Animals; Ceramides; Diglycerides; Humans; Insulin Resistance; Non-alcoholic Fatty Liver Disease
PubMed: 28551355
DOI: 10.1016/j.tips.2017.04.004 -
Cellular and Molecular Life Sciences :... Oct 2015The neutral lipids diacylglycerols (DAGs) are involved in a plethora of metabolic pathways. They function as components of cellular membranes, as building blocks for... (Review)
Review
The neutral lipids diacylglycerols (DAGs) are involved in a plethora of metabolic pathways. They function as components of cellular membranes, as building blocks for glycero(phospho)lipids, and as lipid second messengers. Considering their central role in multiple metabolic processes and signaling pathways, cellular DAG levels require a tight regulation to ensure a constant and controlled availability. Interestingly, DAG species are versatile in their chemical structure. Besides the different fatty acid species esterified to the glycerol backbone, DAGs can occur in three different stereo/regioisoforms, each with unique biological properties. Recent scientific advances have revealed that DAG metabolizing enzymes generate and distinguish different DAG isoforms, and that only one DAG isoform holds signaling properties. Herein, we review the current knowledge of DAG stereochemistry and their impact on cellular metabolism and signaling. Further, we describe intracellular DAG turnover and its stereochemistry in a 3-pool model to illustrate the spatial and stereochemical separation and hereby the diversity of cellular DAG metabolism.
Topics: Animals; Cell Membrane; Diglycerides; Insulin; Metabolic Networks and Pathways; Mice; Models, Biological; Signal Transduction; Stereoisomerism; Type C Phospholipases
PubMed: 26153463
DOI: 10.1007/s00018-015-1982-3 -
Disease Models & Mechanisms Nov 2022Xanthohumol (XN) improves cognition of wild-type rodents on a high-fat diet (HFD). Bile acids and ceramide levels in the liver and hippocampus might be linked to these...
Xanthohumol (XN) improves cognition of wild-type rodents on a high-fat diet (HFD). Bile acids and ceramide levels in the liver and hippocampus might be linked to these effects. XN modulates activity of the nuclear farnesoid X receptor (FXR; also known as NR1H4), the primary receptor for bile acids. To determine the role of FXR in the liver and intestine in mediating the effects of XN on cognitive performance, mice with intestine- and liver-specific FXR ablation (FXRIntestine-/- and FXRLiver-/-, respectively) on an HFD or an HFD containing XN were cognitively tested. XN improved cognitive performance in a genotype- and sex-dependent manner, with improved task learning in females (specifically wild-type), reversal learning in males (specifically wild-type and FXRIntestine-/- mutant) and spatial learning (both sexes). XN increased hippocampal diacylglycerol and sphingomyelin levels in females but decreased them in males. XN increased the ratio of shorter-chain to longer-chain ceramides and hexaceramides. Higher diacylglycerol and lower longer-chain ceramide and hexaceramide levels were linked to improved cognitive performance. Thus, the beneficial sex-dependent cognitive effects of XN are linked to changes in hippocampal diacylglycerol and ceramide levels. This article has an associated First Person interview with the first author of the paper.
Topics: Male; Mice; Animals; Diet, High-Fat; Diglycerides; Liver; Bile Acids and Salts; Ceramides; Cognition; Mice, Inbred C57BL
PubMed: 36353888
DOI: 10.1242/dmm.049820