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Advances in Experimental Medicine and... Jun 2024Insects need to transport lipids through the aqueous medium of the hemolymph to the organs in demand, after they are absorbed by the intestine or mobilized from the...
Insects need to transport lipids through the aqueous medium of the hemolymph to the organs in demand, after they are absorbed by the intestine or mobilized from the lipid-producing organs. Lipophorin is a lipoprotein present in insect hemolymph, and is responsible for this function. A single gene encodes an apolipoprotein that is cleaved to generate apolipophorin I and II. These are the essential protein constituents of lipophorin. In some physiological conditions, a third apolipoprotein of different origin may be present. In most insects, lipophorin transports mainly diacylglycerol and hydrocarbons, in addition to phospholipids. The fat body synthesizes and secretes lipophorin into the hemolymph, and several signals, such as nutritional, endocrine, or external agents, can regulate this process. However, the main characteristic of lipophorin is the fact that it acts as a reusable shuttle, distributing lipids between organs without being endocytosed or degraded in this process. Lipophorin interacts with tissues through specific receptors of the LDL receptor superfamily, although more recent results have shown that other proteins may also be involved. In this chapter, we describe the lipophorin structure in terms of proteins and lipids, in addition to reviewing what is known about lipoprotein synthesis and regulation. In addition, we reviewed the results investigating lipophorin's function in the movement of lipids between organs and the function of lipophorin receptors in this process.
PubMed: 38874888
DOI: 10.1007/5584_2024_806 -
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 -
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 -
Cells Sep 2023Canonical transient receptor potential 3 (TRPC3) channel is a non-selective cation permeable channel that plays an essential role in calcium signalling. TRPC3 is highly... (Review)
Review
Canonical transient receptor potential 3 (TRPC3) channel is a non-selective cation permeable channel that plays an essential role in calcium signalling. TRPC3 is highly expressed in the brain and also found in endocrine tissues and smooth muscle cells. The channel is activated directly by binding of diacylglycerol downstream of G-protein coupled receptor activation. In addition, TRPC3 is regulated by endogenous factors including Ca ions, other endogenous lipids, and interacting proteins. The molecular and structural mechanisms underlying activation and regulation of TRPC3 are incompletely understood. Recently, several high-resolution cryogenic electron microscopy structures of TRPC3 and the closely related channel TRPC6 have been resolved in different functional states and in the presence of modulators, coupled with mutagenesis studies and electrophysiological characterisation. Here, we review the recent literature which has advanced our understanding of the complex mechanisms underlying modulation of TRPC3 by both endogenous and exogenous factors. TRPC3 plays an important role in Ca homeostasis and entry into cells throughout the body, and both pathological variants and downstream dysregulation of TRPC3 channels have been associated with a number of diseases. As such, TRPC3 may be a valuable therapeutic target, and understanding its regulatory mechanisms will aid future development of pharmacological modulators of the channel.
Topics: Brain; Calcium Signaling; Cardiac Electrophysiology; Homeostasis; Mutagenesis
PubMed: 37759438
DOI: 10.3390/cells12182215 -
Molecules (Basel, Switzerland) Jul 2023Phosphatidylcholine-specific phospholipase C (PC-PLC) is an enzyme that catalyzes the formation of the important secondary messengers phosphocholine and diacylglycerol... (Review)
Review
Phosphatidylcholine-specific phospholipase C (PC-PLC) is an enzyme that catalyzes the formation of the important secondary messengers phosphocholine and diacylglycerol (DAG) from phosphatidylcholine. Although PC-PLC has been linked to the progression of many pathological conditions, including cancer, atherosclerosis, inflammation and neuronal cell death, studies of PC-PLC on the protein level have been somewhat neglected with relatively scarce data. To date, the human gene expressing PC-PLC has not yet been found, and the only protein structure of PC-PLC that has been solved was from (PC-PLC). Nonetheless, there is evidence for PC-PLC activity as a human functional equivalent of its prokaryotic counterpart. Additionally, inhibitors of PC-PLC have been developed as potential therapeutic agents. The most notable classes include 2-aminohydroxamic acids, xanthates, ,'-hydroxyureas, phospholipid analogues, 1,4-oxazepines, pyrido[3,4-]indoles, morpholinobenzoic acids and univalent ions. However, many medicinal chemistry studies lack evidence for their cellular and in vivo effects, which hampers the progression of the inhibitors towards the clinic. This review outlines the pathological implications of PC-PLC and highlights current progress and future challenges in the development of PC-PLC inhibitors from the literature.
Topics: Humans; Type C Phospholipases; Phosphatidylcholines
PubMed: 37570610
DOI: 10.3390/molecules28155637 -
Breast Cancer Research : BCR Oct 2023High mammographic breast density (MBD) is a strong risk factor for breast cancer development, but the biological mechanisms underlying MBD are unclear. Lipids play...
BACKGROUND
High mammographic breast density (MBD) is a strong risk factor for breast cancer development, but the biological mechanisms underlying MBD are unclear. Lipids play important roles in cell differentiation, and perturbations in lipid metabolism are implicated in cancer development. Nevertheless, no study has applied untargeted lipidomics to profile the lipidome of MBD. Through this study, our goal is to characterize the lipidome of MBD in premenopausal women.
METHODS
Premenopausal women were recruited during their annual screening mammogram at the Washington University School of Medicine in St. Louis, MO. Untargeted lipidomic profiling for 982 lipid species was performed at Metabolon (Durham, NC®), and volumetric measures of MBD (volumetric percent density (VPD), dense volume (DV), and non-dense volume (NDV)) was assessed using Volpara 1.5 (Volpara Health®). We performed multivariable linear regression models to investigate the associations of lipid species with MBD and calculated the covariate-adjusted least square mean of MBD by quartiles of lipid species. MBD measures were log transformed, and lipid species were standardized. Linear coefficients of MBD were back-transformed and considered significant if the Bonferroni corrected p-value was < 0.05.
RESULTS
Of the 705 premenopausal women, 72% were non-Hispanic white, and 23% were non-Hispanic black. Mean age, and BMI were 46 years and 30 kg/m, respectively. Fifty-six lipid species were significantly associated with VPD (52 inversely and 4 positively). The lipid species with positive associations were phosphatidylcholine (PC)(18:1/18:1), lysophosphatidylcholine (LPC)(18:1), lactosylceramide (LCER)(14:0), and phosphatidylinositol (PI)(18:1/18:1). VPD increased across quartiles of PI(18:1/18:1): (Q1 = 7.5%, Q2 = 7.7%, Q3 = 8.4%, Q4 = 9.4%, Bonferroni p-trend = 0.02). The lipid species that were inversely associated with VPD were mostly from the triacylglycerol (N = 43) and diacylglycerol (N = 7) sub-pathways. Lipid species explained some of the variation in VPD. The inclusion of lipid species increased the adjusted R from 0.45, for a model that includes known determinants of VPD, to 0.59.
CONCLUSIONS
We report novel lipid species that are associated with MBD in premenopausal women. Studies are needed to validate our results and the translational potential.
Topics: Female; Humans; Breast Density; Breast Neoplasms; Lipidomics; Mammography; Risk Factors; Lipids
PubMed: 37814330
DOI: 10.1186/s13058-023-01725-1 -
British Journal of Pharmacology Sep 2023G-protein-coupled receptors (GPCRs) constitute the largest family of membrane receptors, and are involved in the transmission of a variety of extracellular stimuli such... (Review)
Review
G-protein-coupled receptors (GPCRs) constitute the largest family of membrane receptors, and are involved in the transmission of a variety of extracellular stimuli such as hormones, neurotransmitters, light and odorants into intracellular responses. They regulate every aspect of physiology and, for this reason, about one third of all marketed drugs target these receptors. Classically, upon binding to their agonist, GPCRs are thought to activate G-proteins from the plasma membrane and to stop signalling by subsequent desensitisation and endocytosis. However, accumulating evidence indicates that, upon internalisation, some GPCRs can continue to activate G-proteins in endosomes. Importantly, this signalling from endomembranes mediates alternative cellular responses other than signalling at the plasma membrane. Endosomal G-protein signalling and its physiological relevance have been abundantly documented for Gα - and Gα -coupled receptors. Recently, some Gα -coupled receptors have been reported to activate Gα on endosomes and mediate important cellular processes. However, several questions relative to the series of cellular events required to translate endosomal Gα activation into cellular responses remain unanswered and constitute a new conundrum. How are these responses in endosomes mediated in the quasi absence of the substrate for the canonical Gα -activated effector? Is there another effector? Is there another substrate? If so, how does this alternative endosomal effector or substrate produce a downstream signal? This review aims to unravel and discuss these important questions, and proposes possible routes of investigation.
PubMed: 37740273
DOI: 10.1111/bph.16248 -
Journal of Thrombosis and Thrombolysis Nov 2023Metabolites are reliable biomarkers for many diseases. However, their role in acute ischemic stroke (AIS) pathogenesis is not well understood. In this systematic review... (Review)
Review
Metabolites are reliable biomarkers for many diseases. However, their role in acute ischemic stroke (AIS) pathogenesis is not well understood. In this systematic review we aim to evaluate the current literature on the presence of metabolites in thrombi retrieved by mechanical thrombectomy from AIS patients. Following the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) 2020 guidelines, we searched OVID Medline, PubMed, OVID Embase, Scopus, and Web of Science until July 13, 2022. Metabolites lists were extracted, and pathway analysis was performed in MetaboAnalyst database. Four articles listing metabolites were included in this systematic review. D-Glucose, diacylglycerol, phytosphingosine, galabiosylceramide, glucosylceramide and 4-hydroxynonenal were reported to be associated with clots. Metabolomics data analysis showed that glycolysis, lactose, and sphingolipid metabolism pathways were enriched. In conclusion, results of the present study show that the thrombi niche has a glycolytic phenotype. Future studies should work to better understand the metabolic properties of AIS thrombi.
Topics: Humans; Stroke; Ischemic Stroke; Thrombosis; Biomarkers; Phenotype; Brain Ischemia
PubMed: 37580625
DOI: 10.1007/s11239-023-02869-9 -
PloS One 2023Valproate (valproic acid, VPA), a drug for the treatment of epilepsy and bipolar disorder, causes liver steatosis with enhanced oxidative stress. Accumulating evidences...
Valproate (valproic acid, VPA), a drug for the treatment of epilepsy and bipolar disorder, causes liver steatosis with enhanced oxidative stress. Accumulating evidences exhibite that gut microbiota plays an important role in progression of nonalcoholic fatty liver disease (NAFLD). However, whether gut microbiota contributes to VPA-caused hepatic steatosis needs to be elucidated. A mixture of five probiotics was selected to investigate their effects on liver steatosis and oxidative stress in mice orally administered VPA for 30 days. Probiotics treatment significantly attenuated the hepatic lipid accumulation in VPA-treated mice via inhibiting the expression of cluster of differentiation 36 (CD36) and distinct diacylglycerol acyltransferase 2 (DGAT2). Meanwhile, probiotics exerted a protective effect against VPA-induced oxidative stress by decreasing the pro-oxidant cytochrome P450 2E1 (CYP2E1) level and activating the Nrf2/antioxidant enzyme pathway. Moreover, VPA treatment altered the relative abundance of gut microbiota at the phylum, family and genera levels, while probiotics partially restored these changes. Spearman's correlation analysis showed that several specific genera and family were significantly correlated with liver steatosis and oxidative stress-related indicators. These results suggest that probiotics exert their health benefits in the abrogation of liver steatosis and oxidative stress in VPA-treated mice by manipulating the microbial homeostasis.
Topics: Mice; Animals; Valproic Acid; Liver; Non-alcoholic Fatty Liver Disease; Oxidative Stress; Probiotics
PubMed: 37971986
DOI: 10.1371/journal.pone.0294363 -
Food Science & Nutrition Oct 2023(Wangenh.) K. Koch, nuts are a renowned health food. However, there are many cultivars of this nut tree, and their mature kernel lipid composition has not been...
(Wangenh.) K. Koch, nuts are a renowned health food. However, there are many cultivars of this nut tree, and their mature kernel lipid composition has not been thoroughly studied. Therefore, we used liquid chromatography-mass spectrometry (LC-MS) to analyze the lipid composition of mature nuts of five cultivars In the mature kernels of all cultivars, there were 58 lipid types which were mainly composed of glycerolipids (c. 65%) and phospholipids (>30%). Triacylglycerol (TG) accounted for the largest proportion of mature nuts of all cultivars, exceeding 50%; and diacylglycerol (DG), ceramide (Cer), phosphatidylcholine (PC), and phosphatidylethanolamine (PE) were also relatively high. Additionally, nuts contain fatty acids, mainly oleic, linoleic, and linolenic acids. Our research provides a new perspective for the processing and utilization of plant and edible oils, and for the use of kernels in the development of medicine and food science.
PubMed: 37823132
DOI: 10.1002/fsn3.3572