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The Journal of Clinical Endocrinology... Mar 2022Peripheral neuropathy (PN) is a frequent prediabetes and type 2 diabetes (T2D) complication. Multiple clinical studies reveal that obesity and dyslipidemia can also... (Observational Study)
Observational Study
CONTEXT
Peripheral neuropathy (PN) is a frequent prediabetes and type 2 diabetes (T2D) complication. Multiple clinical studies reveal that obesity and dyslipidemia can also drive PN progression, independent of glycemia, suggesting a complex interplay of specific metabolite and/or lipid species may underlie PN.
OBJECTIVE
This work aimed to identify the plasma metabolomics and lipidomics signature that underlies PN in an observational study of a sample of individuals with average class 3 obesity.
METHODS
We performed plasma global metabolomics and targeted lipidomics on obese participants with (n = 44) and without PN (n = 44), matched for glycemic status, vs lean nonneuropathic controls (n = 43). We analyzed data by Wilcoxon, logistic regression, partial least squares-discriminant analysis, and group-lasso to identify differential metabolites and lipids by obesity and PN status. We also conducted subanalysis by prediabetes and T2D status.
RESULTS
Lean vs obese comparisons, regardless of PN status, identified the most significant differences in gamma-glutamyl and branched-chain amino acid metabolism from metabolomics analysis and triacylglycerols from lipidomics. Stratification by PN status within obese individuals identified differences in polyamine, purine biosynthesis, and benzoate metabolism. Lipidomics found diacylglycerols as the most significant subpathway distinguishing obese individuals by PN status, with additional contributions from phosphatidylcholines, sphingomyelins, ceramides, and dihydroceramides. Stratifying the obese group by glycemic status did not affect discrimination by PN status.
CONCLUSION
Obesity may be as strong a PN driver as prediabetes or T2D in a sample of individuals with average class 3 obesity, at least by plasma metabolomics and lipidomics profile. Metabolic and complex lipid pathways can differentiate obese individuals with and without PN, independent of glycemic status.
Topics: Diabetes Mellitus, Type 2; Humans; Lipidomics; Lipids; Metabolomics; Obesity; Peripheral Nervous System Diseases; Prediabetic State
PubMed: 34878536
DOI: 10.1210/clinem/dgab844 -
Journal of Translational Medicine Mar 2024Lipid metabolism is widely reprogrammed in tumor cells. Lipid droplet is a common organelle existing in most mammal cells, and its complex and dynamic functions in... (Review)
Review
Lipid metabolism is widely reprogrammed in tumor cells. Lipid droplet is a common organelle existing in most mammal cells, and its complex and dynamic functions in maintaining redox and metabolic balance, regulating endoplasmic reticulum stress, modulating chemoresistance, and providing essential biomolecules and ATP have been well established in tumor cells. The balance between lipid droplet formation and catabolism is critical to maintaining energy metabolism in tumor cells, while the process of energy metabolism affects various functions essential for tumor growth. The imbalance of synthesis and catabolism of fatty acids in tumor cells leads to the alteration of lipid droplet content in tumor cells. Diacylglycerol acyltransferase 1 and diacylglycerol acyltransferase 2, the enzymes that catalyze the final step of triglyceride synthesis, participate in the formation of lipid droplets in tumor cells and in the regulation of cell proliferation, migration and invasion, chemoresistance, and prognosis in tumor. Several diacylglycerol acyltransferase 1 and diacylglycerol acyltransferase 2 inhibitors have been developed over the past decade and have shown anti-tumor effects in preclinical tumor models and improvement of metabolism in clinical trials. In this review, we highlight key features of fatty acid metabolism and different paradigms of diacylglycerol acyltransferase 1 and diacylglycerol acyltransferase 2 activities on cell proliferation, migration, chemoresistance, and prognosis in tumor, with the hope that these scientific findings will have potential clinical implications.
Topics: Animals; Humans; Diacylglycerol O-Acyltransferase; Triglycerides; Lipid Metabolism; Lipogenesis; Cell Proliferation; Neoplasms; Mammals
PubMed: 38500157
DOI: 10.1186/s12967-024-05084-z -
Molecular Oncology Nov 2023Hepatocellular carcinoma (HCC) is largely associated with aberrant activation of Wnt/β-catenin signaling. Nevertheless, how membrane lipid composition is altered in HCC... (Comparative Study)
Comparative Study
Hepatocellular carcinoma (HCC) is largely associated with aberrant activation of Wnt/β-catenin signaling. Nevertheless, how membrane lipid composition is altered in HCC cells with abnormal Wnt signaling remains elusive. Here, by exploiting comprehensive lipidome profiling, we unravel the membrane lipid composition of six different HCC cell lines with mutations in components of Wnt/β-catenin signaling, leading to differences in their endogenous signaling activity. Among the differentially regulated lipids are diacylglycerol (DAG) and ceramide, which were downregulated at the membrane of HCC cells after Wnt3a treatment. DAG and ceramide enhanced Wnt/β-catenin signaling by inducing caveolin-mediated endocytosis of the canonical Wnt-receptor complex, while their depletion suppressed the signaling activity along with a reduction of caveolin-mediated endocytosis in SNU475 and HepG2 cells. Moreover, depletion of DAG and ceramide significantly impeded the proliferation, tumor growth, and in vivo migration capacity of SNU475 and HepG2 cells. This study, by pioneering plasma membrane lipidome profiling in HCC cells, exhibits the remarkable potential of lipids to correct dysregulated signaling pathways in cancer and stop abnormal tumor growth.
Topics: Humans; beta Catenin; Carcinoma, Hepatocellular; Caveolins; Cell Line, Tumor; Cell Proliferation; Ceramides; Diglycerides; Lipidomics; Liver Neoplasms; Wnt Signaling Pathway
PubMed: 37699867
DOI: 10.1002/1878-0261.13520 -
Proceedings of the National Academy of... Dec 2023Gastroenteritis is among the leading causes of mortality globally in infants and young children, with rotavirus (RV) causing ~258 million episodes of diarrhea and...
Gastroenteritis is among the leading causes of mortality globally in infants and young children, with rotavirus (RV) causing ~258 million episodes of diarrhea and ~128,000 deaths annually in infants and children. RV-induced mechanisms that result in diarrhea are not completely understood, but malabsorption is a contributing factor. RV alters cellular lipid metabolism by inducing lipid droplet (LD) formation as a platform for replication factories named viroplasms. A link between LD formation and gastroenteritis has not been identified. We found that diacylglycerol O-acyltransferase 1 (DGAT1), the terminal step in triacylglycerol synthesis required for LD biogenesis, is degraded in RV-infected cells by a proteasome-mediated mechanism. RV-infected DGAT1-silenced cells show earlier and increased numbers of LD-associated viroplasms per cell that translate into a fourfold-to-fivefold increase in viral yield ( < 0.05). Interestingly, DGAT1 deficiency in children is associated with diarrhea due to altered trafficking of key ion transporters to the apical brush border of enterocytes. Confocal microscopy and immunoblot analyses of RV-infected cells and DGAT1 human intestinal enteroids (HIEs) show a decrease in expression of nutrient transporters, ion transporters, tight junctional proteins, and cytoskeletal proteins. Increased phospho-eIF2α (eukaryotic initiation factor 2 alpha) in DGAT1 HIEs, and RV-infected cells, indicates a mechanism for malabsorptive diarrhea, namely inhibition of translation of cellular proteins critical for nutrient digestion and intestinal absorption. Our study elucidates a pathophysiological mechanism of RV-induced DGAT1 deficiency by protein degradation that mediates malabsorptive diarrhea, as well as a role for lipid metabolism, in the pathogenesis of gastroenteritis.
Topics: Child; Infant; Humans; Child, Preschool; Rotavirus; Diacylglycerol O-Acyltransferase; Virus Replication; Gastroenteritis; Diarrhea; Rotavirus Infections
PubMed: 38079544
DOI: 10.1073/pnas.2302161120 -
The Journal of Biological Chemistry Jun 2020The transient receptor potential vanilloid 1 (TRPV1) channel is activated by heat and by capsaicin, the pungent compound in chili peppers. Calcium influx through TRPV1...
The transient receptor potential vanilloid 1 (TRPV1) channel is activated by heat and by capsaicin, the pungent compound in chili peppers. Calcium influx through TRPV1 has been shown to activate a calcium-sensitive phospholipase C (PLC) enzyme and to lead to a robust decrease in phosphatidylinositol 4,5-bisphosphate [PI(4,5)P] levels, which is a major contributor to channel desensitization. Diacylglycerol (DAG), the product of the PLC-catalyzed PI(4,5)P hydrolysis, activates protein kinase C (PKC). PKC is known to potentiate TRPV1 activity during activation of G protein-coupled receptors, but it is not known whether DAG modulates TRPV1 during desensitization. We found here that inhibition of diacylglycerol kinase (DAGK) enzymes reduces desensitization of native TRPV1 in dorsal root ganglion neurons as well as of recombinant TRPV1 expressed in HEK293 cells. The effect of DAGK inhibition was eliminated by mutating two PKC-targeted phosphorylation sites, Ser-502 and Ser-800, indicating involvement of PKC. TRPV1 activation induced only a small and transient increase in DAG levels, unlike the robust and more sustained increase induced by muscarinic receptor activation. DAGK inhibition substantially increased the DAG signal evoked by TRPV1 activation but not that evoked by M1 muscarinic receptor activation. Our results show that Ca influx through TRPV1 activates PLC and DAGK enzymes and that the latter limits formation of DAG and negatively regulates TRPV1 channel activity. Our findings uncover a role of DAGK in ion channel regulation.
Topics: Animals; Calcium; Capsaicin; Cell Membrane; Cytoplasm; Diacylglycerol Kinase; Diglycerides; HEK293 Cells; Humans; Ion Channel Gating; Mice, Inbred C57BL; Models, Biological; Phosphatidylinositol 4,5-Diphosphate; Protein Kinase C; Protein Kinase Inhibitors; Rats; Ritanserin; TRPV Cation Channels
PubMed: 32345612
DOI: 10.1074/jbc.RA119.012505 -
The Journal of Biological Chemistry Apr 2024Lipids have been previously implicated in the lifecycle of neuroinvasive viruses. However, the role of lipids in programmed cell death and the relationship between...
Lipids have been previously implicated in the lifecycle of neuroinvasive viruses. However, the role of lipids in programmed cell death and the relationship between programmed cell death and lipid droplets (LDs) in neuroinvasive virus infection remains unclear. Here, we found that the infection of neuroinvasive virus, such as rabies virus and encephalomyocarditis virus could enhance the LD formation in N2a cells, and decreasing LDs production by targeting diacylglycerol acyltransferase could suppress viral replication. The lipidomics analysis revealed that arachidonic acid (AA) was significantly increased after reducing LD formation by restricting diacylglycerol acyltransferase, and AA was further demonstrated to induce ferroptosis to inhibit neuroinvasive virus replication. Moreover, lipid peroxidation and viral replication inhibition could be significantly alleviated by a ferroptosis inhibitor, ferrostatin-1, indicating that AA affected neuroinvasive virus replication mainly through inducing ferroptosis. Furthermore, AA was demonstrated to activate the acyl-CoA synthetase long-chain family member 4-lysophosphatidylcholine acyltransferase 3-cytochrome P450 oxidoreductase axis to induce ferroptosis. Our findings highlight novel cross-talks among viral infection, LDs, and ferroptosis for the first time, providing a potential target for antiviral drug development.
Topics: Ferroptosis; Lipid Droplets; Animals; Virus Replication; Mice; Arachidonic Acid; Encephalomyocarditis virus; Diacylglycerol O-Acyltransferase; Lipid Peroxidation; Coenzyme A Ligases; Cell Line, Tumor; Humans
PubMed: 38490434
DOI: 10.1016/j.jbc.2024.107168 -
Lipids in Health and Disease May 2020Protein kinase C (PKC) and Protein kinase D (PKD) isoforms can sense diacylglycerol (DAG) generated in the different cellular compartments in various physiological... (Review)
Review
Protein kinase C (PKC) and Protein kinase D (PKD) isoforms can sense diacylglycerol (DAG) generated in the different cellular compartments in various physiological processes. DAG accumulates in multiple organs of the obese subjects, which leads to the disruption of metabolic homeostasis and the development of diabetes as well as associated diseases. Multiple studies proved that aberrant activation of PKCs and PKDs contributes to the development of metabolic diseases. DAG-sensing PKC and PKD isoforms play a crucial role in the regulation of metabolic homeostasis and therefore might serve as targets for the treatment of metabolic disorders such as obesity and diabetes.
Topics: Animals; Diabetes Mellitus; Diglycerides; Glucose; Humans; Insulin; Lipid Metabolism; Obesity; Protein Kinase C; Signal Transduction
PubMed: 32466765
DOI: 10.1186/s12944-020-01286-8 -
Biochemistry Apr 2021Munc13-1 is a presynaptic active zone protein that acts as a master regulator of synaptic vesicle priming and neurotransmitter release in the brain. It has been...
Munc13-1 is a presynaptic active zone protein that acts as a master regulator of synaptic vesicle priming and neurotransmitter release in the brain. It has been implicated in the pathophysiology of several neurodegenerative diseases. Diacylglycerol and phorbol ester activate Munc13-1 by binding to its C1 domain. The objective of this study is to identify the structural determinants of ligand binding activity of the Munc13-1 C1 domain. Molecular docking suggested that residues Trp-588, Ile-590, and Arg-592 of Munc13-1 are involved in ligand interactions. To elucidate the role of these three residues in ligand binding, we generated W588A, I590A, and R592A mutants in full-length Munc13-1, expressed them as GFP-tagged proteins in HT22 cells, and measured their ligand-induced membrane translocation by confocal microscopy and immunoblotting. The extent of 1,2-dioctanoyl--glycerol (DOG)- and phorbol ester-induced membrane translocation decreased in the following order: wild type > I590A > W588A > R592A and wild type > W588A > I590A > R592A, respectively. To understand the effect of the mutations on ligand binding, we also measured the DOG binding affinity of the isolated wild-type C1 domain and its mutants in membrane-mimicking micelles using nuclear magnetic resonance methods. The DOG binding affinity decreased in the following order: wild type > I590A > R592A. No binding was detected for W588A with DOG in micelles. This study shows that Trp-588, Ile-590, and Arg-592 are essential determinants for the activity of Munc13-1 and the effects of the three residues on the activity are ligand-dependent. This study bears significance for the development of selective modulators of Munc13-1.
Topics: Binding Sites; Cell Line; Diglycerides; Humans; Models, Molecular; Nerve Tissue Proteins; Protein Binding; Protein Conformation
PubMed: 33818064
DOI: 10.1021/acs.biochem.1c00165 -
Frontiers in Plant Science 2020In an alternative pathway to acyl-CoA: diacylglycerol acyltransferase (DGAT)-mediated triacylglycerol (TAG) synthesis from diacylglycerol, phospholipid:diacylglycerol...
In an alternative pathway to acyl-CoA: diacylglycerol acyltransferase (DGAT)-mediated triacylglycerol (TAG) synthesis from diacylglycerol, phospholipid:diacylglycerol acyltransferase (PDAT) utilizes not acyl-CoA but an acyl group from sn-2 position of a phospholipid, to form TAG. The enzyme's activity matches DGAT's in a number of plant species, however its main function in plants (especially in vegetative tissue) is debatable. In the presented study, we cultivated -overexpressing, knockout and wild-type lines of through their whole lifecycle. overexpression prolonged Arabidopsis lifespan in comparison to wild-type plants, whereas knocking out accelerated the plant's senescence. After subjecting the 3-week old seedlings of the studied lines (grown ) to 2-h heat stress (40°C) and then growing them for one more week in standard conditions, the difference in weight between wild-type and 1-overexpressing lines increased in comparison to the difference between plants grown only in optimal conditions. In another experiment all lines exposed to 2-week cold stress experienced loss of pigment, except for 1-overexpressing lines, which green rosettes additionally weighed 4 times more than wild-type. Our results indicate that plants depleted of are more susceptible to cold exposure, while overexpression grants plants a certain heat and cold resilience. Since it was shown, that lysophospholipids may be intertwined with stress response, we decided to also conduct assays of acyl-CoA:lysophosphatidylcholine acyltransferase (LPCAT) and acylCoA:lysophosphatidylethanolamine acyltransferase (LPEAT) activity in microsomal fractions from the -overexpressing Arabidopsis lines in standard conditions. The results show significant increase in LPEAT and LPCAT activity in comparison to wild-type plants. -overexpressing lines' rosettes also present twice as high expression of in comparison to control. The presented study shows how much heightened expression of augments plant condition after stress and extends its lifespan.
PubMed: 33381143
DOI: 10.3389/fpls.2020.611897 -
Developmental Biology Jul 2022External environmental cues can have significant impacts on the timing and outcomes of animal development. For the swimming larvae of many marine invertebrates, the...
External environmental cues can have significant impacts on the timing and outcomes of animal development. For the swimming larvae of many marine invertebrates, the presence of specific surface-bound bacteria are important cues that help larvae identify a suitable location on the sea floor for metamorphosis and adult life. While metamorphosis in response to bacteria occurs in diverse animals from across the animal tree of life, we know little about the signal transduction cascades stimulated at the onset of metamorphosis upon their interaction with bacteria. The metamorphosis of a model tubeworm, Hydroides elegans, is triggered by the bacterium Pseudoalteromonas luteoviolacea which produces a stimulatory protein called Mif1. In this work, we define three key nodes in a signaling cascade promoting Hydroides metamorphosis in response to Mif1. Using metabolomic profiling, we find that the stimulation of Hydroides larvae by P. luteoviolacea leads to an increase in diacylglycerol during the initiation of metamorphosis, and that Mif1 is necessary for this upregulation. Genomic and pharmacological examination suggests that diacylglycerol triggers a phosphotransferase signaling cascade involving Protein Kinase C (PKC) and Mitogen-Activated Protein Kinase (MAPK), to induce Hydroides metamorphosis. Additionally, Mif1 activates the expression of two nuclear hormone receptors, HeNHR1 and HeNHR2 in the cerebral ganglia of Hydroides larvae. Our results define a post-translational signal transduction pathway mediating bacteria-stimulated metamorphosis in a model invertebrate animal.
Topics: Animals; Diglycerides; Larva; Metamorphosis, Biological; Mitogen-Activated Protein Kinases; Polychaeta; Protein Kinase C; Signal Transduction
PubMed: 35500661
DOI: 10.1016/j.ydbio.2022.04.009