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Bone Nov 2022Sarcopenia is an age-related disease associated with loss of muscle mass and strength. This geriatric syndrome predisposes elderly individuals to a disability, falls,... (Review)
Review
Sarcopenia is an age-related disease associated with loss of muscle mass and strength. This geriatric syndrome predisposes elderly individuals to a disability, falls, fractures, and death. Fat infiltration in muscle is one of the hallmarks of sarcopenia and aging. Alterations in fatty acid (FA) metabolism are evident in aging, type 2 diabetes, and obesity, with the accumulation of lipids inside muscle cells contributing to muscle insulin resistance and ceramide accumulation. These lipids include diacylglycerol, lipid droplets, intramyocellular lipids, intramuscular triglycerides, and polyunsaturated fatty acids (PUFAs). In this review, we examine the regulation of lipid metabolism in skeletal muscle, including lipid metabolization and storage, intervention, and the types of lipases expressed in skeletal muscle responsible for the breakdown of adipose triglyceride fats. In addition, we address the role of FAs in sarcopenia and the potential benefits of PUFAs.
Topics: Aged; Ceramides; Diabetes Mellitus, Type 2; Diglycerides; Fatty Acids; Fatty Acids, Unsaturated; Humans; Insulin Resistance; Lipid Metabolism; Muscle, Skeletal; Sarcopenia; Triglycerides
PubMed: 36007811
DOI: 10.1016/j.bone.2022.116539 -
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 -
Advances in Biological Regulation May 2023Diacylglycerol (DAG) and phosphatidic acid (PtdOH) play important roles in a variety of signaling cascades (Carrasco and Merida, 2007; Stace and Ktistakis, 2006).... (Review)
Review
Diacylglycerol (DAG) and phosphatidic acid (PtdOH) play important roles in a variety of signaling cascades (Carrasco and Merida, 2007; Stace and Ktistakis, 2006). Therefore, the physiological roles and regulatory mechanisms controlling the levels of these lipids are important. One class of enzymes capable of coordinating the levels of these two lipids are the diacylglycerol kinases (DGKs). DGKs catalyze the transfer of the γ-phosphate of ATP to the hydroxyl group of DAG which generates PtdOH(Merida et al., 2008; Sakane et al., 2007). As DGKs reciprocally modulate the relative levels of these two signaling lipids, it is not surprising that there is increasing interest in understanding the mechanism underlying the catalysis and regulation of these kinases. While post-translational modifications (PTMs) are often involved in enzyme regulation, there is surprisingly little information regarding the PTMs on these enzymes and their roles in modulating their activity and function. In this review, we will summarize what is known about one PTM on DGKs, phosphorylation, and the possible functions of this modification.
Topics: Humans; Diglycerides; Phosphorylation; Diacylglycerol Kinase
PubMed: 36508895
DOI: 10.1016/j.jbior.2022.100941 -
Cell Jul 2018The inner nuclear membrane (INM) encases the genome and is fused with the outer nuclear membrane (ONM) to form the nuclear envelope. The ONM is contiguous with the...
The inner nuclear membrane (INM) encases the genome and is fused with the outer nuclear membrane (ONM) to form the nuclear envelope. The ONM is contiguous with the endoplasmic reticulum (ER), the main site of phospholipid synthesis. In contrast to the ER and ONM, evidence for a metabolic activity of the INM has been lacking. Here, we show that the INM is an adaptable membrane territory capable of lipid metabolism. S. cerevisiae cells target enzymes to the INM that can promote lipid storage. Lipid storage involves the synthesis of nuclear lipid droplets from the INM and is characterized by lipid exchange through Seipin-dependent membrane bridges. We identify the genetic circuit for nuclear lipid droplet synthesis and a role of these organelles in regulating this circuit by sequestration of a transcription factor. Our findings suggest a link between INM metabolism and genome regulation and have potential relevance for human lipodystrophy.
Topics: Cell Nucleus; Diglycerides; Endoplasmic Reticulum; Lipid Droplets; Lipid Metabolism; Lipids; Membrane Lipids; Membrane Proteins; Nuclear Envelope; Phosphatidic Acids; Saccharomyces cerevisiae
PubMed: 29937227
DOI: 10.1016/j.cell.2018.05.047 -
Biochimica Et Biophysica Acta.... Nov 2017The glycerophospholipids phosphatidylethanolamine, phosphatidylglycerol (PG), and cardiolipin (CL) are major structural components of bacterial membranes. In some... (Review)
Review
The glycerophospholipids phosphatidylethanolamine, phosphatidylglycerol (PG), and cardiolipin (CL) are major structural components of bacterial membranes. In some bacteria, phosphatidylcholine or phosphatidylinositol and its derivatives form part of the membrane. PG or CL can be modified with the amino acid residues lysine, alanine, or arginine. Diacylglycerol is the lipid anchor from which syntheses of phosphorus-free glycerolipids, such as glycolipids, sulfolipids, or homoserine-derived lipids initiate. Many membrane lipids are subject to turnover and some of them are recycled. Other lipids associated with the membrane include isoprenoids and their derivatives such as hopanoids. Ornithine-containing lipids are widespread in Bacteria but absent in Archaea and Eukarya. Some lipids are probably associated exclusively with the outer membrane of many bacteria, i.e. lipopolysaccharides, sphingolipids, or sulfonolipids. For certain specialized membrane functions, specific lipid structures might be required. Upon cyst formation in Azotobacter vinelandii, phenolic lipids are accumulated in the membrane. Anammox bacteria contain ladderane lipids in the membrane surrounding the anammoxosome organelle, presumably to impede the passage of highly toxic compounds generated during the anammox reaction. Considering that present knowledge on bacterial lipids was obtained from only a few bacterial species, we are probably only starting to unravel the full scale of lipid diversity in bacteria. This article is part of a Special Issue entitled: Bacterial Lipids edited by Russell E. Bishop.
Topics: Bacteria; Diglycerides; Glycerophospholipids; Lipogenesis; Membrane Lipids; Molecular Structure; Structure-Activity Relationship
PubMed: 27760387
DOI: 10.1016/j.bbalip.2016.10.007 -
Advances in Biological Regulation Jan 2017Diacylglycerol kinases (DGK) are a family of enzymes that catalyze the transformation of diacylglycerol into phosphatidic acid. In T lymphocytes, DGKα and ζ limit the... (Review)
Review
Diacylglycerol kinases (DGK) are a family of enzymes that catalyze the transformation of diacylglycerol into phosphatidic acid. In T lymphocytes, DGKα and ζ limit the activation of the PLCγ/Ras/ERK axis, providing a critical checkpoint to inhibit T cell responses. Upregulation of these isoforms limits Ras activation, leading to hypo-responsive, anergic states similar to those caused by tumors. Recent studies have identified DGKα upregulation in tumor lymphocyte infiltrates, and cells from DGKα and ζ deficient mice show enhanced antitumor activity, suggesting that limitation of DAG based signals by DGK is used by tumors to evade immune attack. DGKα expression is low or even absent in other healthy cells like melanocytes, hepatocytes or neurons. Expression of this isoform, nevertheless is upregulated in melanoma, hepatocarcinoma and glioblastoma where DGKα contributes to the acquisition of tumor metastatic traits. A model thus emerges where tumor milieu fosters DGKα expression in tumors as well as in tumor infiltrating lymphocytes with opposite consequences. Here we review the mechanisms and targets that facilitate tumor "addiction" to DGKα, and discuss its relevance in the more advanced forms of cancer for tumor immune evasion. A better knowledge of this function offers a new perspective in the search of novel approaches to prevent inhibition of immune attack in cancer. Part of the failure in clinical progress may be attributed to the complexity of the tumor/T lymphocyte interaction. As they develop, tumors use a number of mechanisms to drive endogenous, tumor reactive T cells to a general state of hyporesponsiveness or anergy. A better knowledge of the molecular mechanisms that tumors use to trigger T cell anergic states will greatly help in the advance of immunotherapy research.
Topics: Animals; Clonal Anergy; Diacylglycerol Kinase; Diglycerides; Extracellular Signal-Regulated MAP Kinases; Gene Expression Regulation, Neoplastic; Humans; Mice; Neoplasms; Phosphatidic Acids; Phospholipase C gamma; Signal Transduction; T-Lymphocytes; Tumor Escape; ras Proteins
PubMed: 27697466
DOI: 10.1016/j.jbior.2016.09.005 -
International Journal of Molecular... Sep 2020The diacylglycerol kinase family, which can attenuate diacylglycerol signaling and activate phosphatidic acid signaling, regulates various signaling transductions in the... (Review)
Review
The diacylglycerol kinase family, which can attenuate diacylglycerol signaling and activate phosphatidic acid signaling, regulates various signaling transductions in the mammalian cells. Studies on the regulation of diacylglycerol and phosphatidic acid levels by various enzymes, the identification and characterization of various diacylglycerol and phosphatidic acid-regulated proteins, and the overlap of different diacylglycerol and phosphatidic acid metabolic and signaling processes have revealed the complex and non-redundant roles of diacylglycerol kinases in regulating multiple biochemical and biological networks. In this review article, we summarized recent progress in the complex and non-redundant roles of diacylglycerol kinases, which is expected to aid in restoring dysregulated biochemical and biological networks in various pathological conditions at the bed side.
Topics: Animals; Diabetes Mellitus; Diacylglycerol Kinase; Diglycerides; Humans; Inflammation; Neoplasms; Nervous System Diseases; Phosphatidic Acids; Protein Isoforms; Signal Transduction
PubMed: 32962151
DOI: 10.3390/ijms21186861 -
Nature Communications Jun 2023Lipid droplets (LDs) are dynamic organelles that contain an oil core mainly composed of triglycerides (TAG) that is surrounded by a phospholipid monolayer and...
Lipid droplets (LDs) are dynamic organelles that contain an oil core mainly composed of triglycerides (TAG) that is surrounded by a phospholipid monolayer and LD-associated proteins called perilipins (PLINs). During LD biogenesis, perilipin 3 (PLIN3) is recruited to nascent LDs as they emerge from the endoplasmic reticulum. Here, we analyze how lipid composition affects PLIN3 recruitment to membrane bilayers and LDs, and the structural changes that occur upon membrane binding. We find that the TAG precursors phosphatidic acid and diacylglycerol (DAG) recruit PLIN3 to membrane bilayers and define an expanded Perilipin-ADRP-Tip47 (PAT) domain that preferentially binds DAG-enriched membranes. Membrane binding induces a disorder to order transition of alpha helices within the PAT domain and 11-mer repeats, with intramolecular distance measurements consistent with the expanded PAT domain adopting a folded but dynamic structure upon membrane binding. In cells, PLIN3 is recruited to DAG-enriched ER membranes, and this requires both the PAT domain and 11-mer repeats. This provides molecular details of PLIN3 recruitment to nascent LDs and identifies a function of the PAT domain of PLIN3 in DAG binding.
Topics: Diglycerides; Endoplasmic Reticulum; Lipid Droplets; Lipid Metabolism; Perilipin-1; Perilipin-3; Triglycerides
PubMed: 37268630
DOI: 10.1038/s41467-023-38725-w -
Science Advances Nov 2023Diacylglycerol kinases (DGKs) attenuate diacylglycerol (DAG) signaling by converting DAG to phosphatidic acid, thereby suppressing pathways downstream of T cell receptor...
Diacylglycerol kinases (DGKs) attenuate diacylglycerol (DAG) signaling by converting DAG to phosphatidic acid, thereby suppressing pathways downstream of T cell receptor signaling. Using a dual DGKα/ζ inhibitor (DGKi), tumor-specific CD8 T cells with different affinities (TRP1 and TRP1), and altered peptide ligands, we demonstrate that inhibition of DGKα/ζ can lower the signaling threshold for T cell priming. TRP1 and TRP1 CD8 T cells produced more effector cytokines in the presence of cognate antigen and DGKi. Effector TRP1- and TRP1-mediated cytolysis of tumor cells with low antigen load required antigen recognition, was mediated by interferon-γ, and augmented by DGKi. Adoptive T cell transfer into mice bearing pancreatic or melanoma tumors synergized with single-agent DGKi or DGKi and antiprogrammed cell death protein 1 (PD-1), with increased expansion of low-affinity T cells and increased cytokine production observed in tumors of treated mice. Collectively, our findings highlight DGKα/ζ as therapeutic targets for augmenting tumor-specific CD8 T cell function.
Topics: Mice; Animals; Diglycerides; CD8-Positive T-Lymphocytes; Signal Transduction; Neoplasms; Receptors, Antigen, T-Cell
PubMed: 38000024
DOI: 10.1126/sciadv.adk1853 -
American Journal of Physiology. Lung... Jul 2024Signal transduction by G protein-coupled receptors (GPCRs), receptor tyrosine kinases (RTKs) and immunoreceptors converge at the activation of phospholipase C (PLC) for... (Review)
Review
Signal transduction by G protein-coupled receptors (GPCRs), receptor tyrosine kinases (RTKs) and immunoreceptors converge at the activation of phospholipase C (PLC) for the hydrolysis of phosphatidylinositol 4,5-bisphosphate (PIP) into inositol 1,4,5-trisphosphate (IP) and diacylglycerol (DAG). This is a point for second-messenger bifurcation where DAG via protein kinase C (PKC) and IP via calcium activate distinct protein targets and regulate cellular functions. IP signaling is regulated by multiple calcium influx and efflux proteins involved in calcium homeostasis. A family of lipid kinases belonging to DAG kinases (DGKs) converts DAG to phosphatidic acid (PA), negatively regulating DAG signaling and pathophysiological functions. PA, through a series of biochemical reactions, is recycled to produce new molecules of PIP. Therefore, DGKs act as a central switch in terminating DAG signaling and resynthesis of membrane phospholipids precursor. Interestingly, calcium and PKC regulate the activation of α and ζ isoforms of DGK that are predominantly expressed in airway and immune cells. Thus, DGK forms a feedback and feedforward control point and plays a crucial role in fine-tuning phospholipid stoichiometry, signaling, and functions. In this review, we discuss the previously underappreciated complex and intriguing DAG/DGK-driven mechanisms in regulating cellular functions associated with asthma, such as contraction and proliferation of airway smooth muscle (ASM) cells and inflammatory activation of immune cells. We highlight the benefits of manipulating DGK activity in mitigating salient features of asthma pathophysiology and shed light on DGK as a molecule of interest for heterogeneous diseases such as asthma.
Topics: Asthma; Humans; Diacylglycerol Kinase; Animals; Signal Transduction; Diglycerides; Protein Kinase C
PubMed: 38742284
DOI: 10.1152/ajplung.00091.2024