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Lipids in Health and Disease May 2024Cancer prognosis remains a critical clinical challenge. Lipidomic analysis via mass spectrometry (MS) offers the potential for objective prognostic prediction,... (Review)
Review
Cancer prognosis remains a critical clinical challenge. Lipidomic analysis via mass spectrometry (MS) offers the potential for objective prognostic prediction, leveraging the distinct lipid profiles of cancer patient-derived specimens. This review aims to systematically summarize the application of MS-based lipidomic analysis in prognostic prediction for cancer patients. Our systematic review summarized 38 studies from the past decade that attempted prognostic prediction of cancer patients through lipidomics. Commonly analyzed cancers included colorectal, prostate, and breast cancers. Liquid (serum and urine) and tissue samples were equally used, with liquid chromatography-tandem MS being the most common analytical platform. The most frequently evaluated prognostic outcomes were overall survival, stage, and recurrence. Thirty-eight lipid markers (including phosphatidylcholine, ceramide, triglyceride, lysophosphatidylcholine, sphingomyelin, phosphatidylethanolamine, diacylglycerol, phosphatidic acid, phosphatidylserine, lysophosphatidylethanolamine, lysophosphatidic acid, dihydroceramide, prostaglandin, sphingosine-1-phosphate, phosphatidylinosito, fatty acid, glucosylceramide and lactosylceramide) were identified as prognostic factors, demonstrating potential for clinical application. In conclusion, the potential for developing lipidomics in cancer prognostic prediction was demonstrated. However, the field is still nascent, necessitating future studies for validating and establishing lipid markers as reliable prognostic tools in clinical practice.
Topics: Humans; Prognosis; Neoplasms; Lipidomics; Biomarkers, Tumor; Mass Spectrometry; Female; Lipids; Male; Breast Neoplasms; Prostatic Neoplasms; Lysophospholipids; Colorectal Neoplasms
PubMed: 38796445
DOI: 10.1186/s12944-024-02121-0 -
Neuropsychopharmacology : Official... Dec 2023Endocannabinoids (eCB) and cannabinoid receptor 1 (CB1) play important roles in mediating short- and long-term synaptic plasticity in many brain regions involved in...
Endocannabinoids (eCB) and cannabinoid receptor 1 (CB1) play important roles in mediating short- and long-term synaptic plasticity in many brain regions involved in learning and memory, as well as the reinforcing effects of misused substances. Ethanol-induced plasticity and neuroadaptations predominantly occur in striatal direct pathway projecting medium spiny neurons (dMSNs). It is hypothesized that alterations in eCB neuromodulation may be involved. Recent work has implicated a role of eCB 2-arachidonoylglycerol (2-AG) in the rewarding effects of ethanol. However, there is insufficient research to answer which cellular subtype is responsible for mediating the 2-AG eCB signal that might be involved in the rewarding properties of ethanol and the mechanisms by which that occurs. To examine the role of dMSN mediated 2-AG signaling in ethanol related synaptic transmission and behaviors, we used conditional knockout mice in which the 2-AG-synthesizing enzyme diacylglycerol lipase α (DGLα) was deleted in dMSNs, DGLα. Using acute brain slice photometry and a genetically encoded fluorescent eCB sensor, GRAB to assess real-time eCB mediated activity of sensorimotor inputs from primary motor cortices (M1/M2) to the dorsolateral striatum, we showed that DGLα mice had blunted evoked eCB-mediated presynaptic eCB signaling compared to littermate controls. Furthermore, ethanol induced eCB inhibition was significantly reduced in DGLα deficient mice. Additionally, there was a reduction in the duration of loss of righting reflex (LORR) to a high dose of ethanol in the DGLα mice compared to controls. These mice also showed a male-specific decrease in ethanol preference accompanied by an increase in ethanol-induced water consumption in a voluntary drinking paradigm. There were no significant differences observed in sucrose and quinine consumption between the genotypes. These findings reveal a novel role for dMSN mediated 2-AG signaling in modulating ethanol effects on presynaptic function and behavior.
Topics: Mice; Animals; Male; Synaptic Transmission; Glycerides; Endocannabinoids; Mice, Knockout; Ethanol; Receptor, Cannabinoid, CB1
PubMed: 37528221
DOI: 10.1038/s41386-023-01671-8 -
International Journal of Molecular... Mar 2024Human placenta is an intensively growing tissue. Phosphatidylinositol (PI) and its derivatives are part of the signaling pathway in the regulation of trophoblast cell...
Human placenta is an intensively growing tissue. Phosphatidylinositol (PI) and its derivatives are part of the signaling pathway in the regulation of trophoblast cell differentiation. There are two different enzymes that take part in the direct PI synthesis: phosphatidylinositol synthase (PIS) and inositol exchange enzyme (IE). The presence of PIS is known in the human placenta, but IE activity has not been documented before. In our study, we describe the physiological properties of the two enzymes in vitro. PIS and IE were studied in different Mn and Mg concentrations that enabled us to separate the individual enzyme activities. Enzyme activity was measured by incorporation of 3[H]inositol in human primordial placenta tissue or microsomes. Optimal PIS activity was achieved between 0.5 and 2.0 mM Mn concentration, but higher concentrations inhibit enzyme activity. In the presence of Mg, the enzyme activity increases continuously up to a concentration of 100 mM. PIS was inhibited by nucleoside di- and tri-phosphates. PI production increases between 0.1 and 10 mM Mn concentration. The incorporation of [3H]inositol into PI increased by 57% when adding stabile GTP analog. The described novel pathway of inositol synthesis may provide an additional therapeutic approach of inositol supplementation before and during pregnancy.
Topics: Female; Pregnancy; Humans; Inositol; Phosphatidylinositols; CDP-Diacylglycerol-Inositol 3-Phosphatidyltransferase; Transferases (Other Substituted Phosphate Groups); Placenta
PubMed: 38542419
DOI: 10.3390/ijms25063436 -
International Journal of Genomics 2023Genome-wide association studies (GWAS) are a powerful tool for identifying genomic regions and causative genes associated with economically important traits in dairy... (Review)
Review
Genome-wide association studies (GWAS) are a powerful tool for identifying genomic regions and causative genes associated with economically important traits in dairy cattle, particularly complex traits, such as milk production. This is possible due to advances in next-generation sequencing technology. This review summarized information on identified candidate genes and genomic regions associated with milk production traits in Holstein and its crossbreds from various regions of the world. Milk production traits are important in dairy cattle breeding programs because of their direct economic impact on the industry and their close relationship with nutritional requirements. GWAS has been used in a large number of studies to identify genomic regions and candidate genes associated with milk production traits in dairy cattle. Many genomic regions and candidate genes have already been identified in Holstein and its crossbreds. Genes and single nucleotide polymorphisms (SNPs) that significantly affect milk yield (MY) were found in all autosomal chromosomes except chromosomes 27 and 29. Half of the reported SNPs associated with fat yield and fat percentage were found on chromosome 14. However, a large number of significant SNPs for protein yield (PY) and protein percentage were found on chromosomes 1, 5, and 20. Approximately 155 SNPs with significant influence on multiple milk production traits have been identified. Several promising candidate genes, including diacylglycerol O-acyltransferase 1, plectin, Rho GTPase activating protein 39, protein phosphatase 1 regulatory subunit 16A, and sphingomyelin phosphodiesterase 5 were found to have pleiotropic effects on all five milk production traits. Thus, to improve milk production traits it is of practical relevance to focus on significant SNPs and pleiotropic genes frequently found to affect multiple milk production traits.
PubMed: 37547753
DOI: 10.1155/2023/8497453 -
BioRxiv : the Preprint Server For... Jul 2023Sphingomyelin (SM) is a major component of mammalian cell membranes and particularly abundant in the myelin sheath that surrounds nerve fibers. Its production is...
Sphingomyelin (SM) is a major component of mammalian cell membranes and particularly abundant in the myelin sheath that surrounds nerve fibers. Its production is catalyzed by SM synthases SMS1 and SMS2, which interconvert phosphatidylcholine and ceramide to diacylglycerol and SM in the Golgi and at the plasma membrane, respectively. As the lipids participating in this reaction fulfill both structural and signaling functions, SMS enzymes have considerable potential to influence diverse important cellular processes. The nematode is an attractive model for studying both animal development and human disease. The organism contains five SMS homologues but none of these have been characterized in any detail. Here, we carried out the first systematic analysis of SMS family members in . Using heterologous expression systems, genetic ablation, metabolic labeling and lipidome analyses, we show that harbors at least three distinct SM synthases and one ceramide phosphoethanolamine (CPE) synthase. Moreover, SMS family members have partially overlapping but also unique subcellular distributions and together occupy all principal compartments of the secretory pathway. Our findings shed light on crucial aspects of sphingolipid metabolism in a valuable animal model and opens avenues for exploring the role of SM and its metabolic intermediates in organismal development.
PubMed: 37546869
DOI: 10.1101/2023.07.25.550547 -
Journal of Dairy Science Aug 2023Fatty liver is a major metabolic disorder of high-producing dairy cows during the transition period. In nonruminants, it is well established that insulin-induced gene 1...
Fatty liver is a major metabolic disorder of high-producing dairy cows during the transition period. In nonruminants, it is well established that insulin-induced gene 1 (INSIG1) plays a crucial role in regulating hepatic lipogenesis by controlling the anchoring of sterol regulatory element-binding protein 1 (SREBP-1) on the endoplasmic reticulum along with SREBP cleavage-activating protein (SCAP). Whether the INSIG1-SCAP-SREBP-1c transport axis is affected in cows experiencing fatty liver is unknown. Thus, the aim of this study was to investigate the potential role of INSIG1-SCAP-SREBP-1c axis in the progression of fatty liver in dairy cows. For in vivo experiments, 24 dairy cows at the start of their fourth lactation (median; range 3-5) and 8 d in milk (median; range 4-12 d) were selected into a healthy group [n = 12; triglyceride (TG) content <1%] and a severe fatty liver group (n = 12; TG content >10%) according to their hepatic TG content. Blood samples were collected for detecting serum concentrations of free fatty acids, β-hydroxybutyrate, and glucose. Compared with healthy cows, cows with severe fatty liver had higher serum concentrations of β-hydroxybutyrate and free fatty acids and lower concentration of glucose. Liver biopsies were used to detect the status of INSIG1-SCAP-SREBP-1c axis, and the mRNA expression of SREBP-1c-target lipogenic genes acetyl-CoA carboxylase α (ACACA), fatty acid synthase (FASN), and diacylglycerol acyltransferase 1 (DGAT1). Cows with severe fatty liver had lower protein expression of INSIG1 in the hepatocyte endoplasmic reticulum fraction, greater protein expression of SCAP and precursor SREBP-1c in the hepatocyte Golgi fraction, and greater protein expression of mature SREBP-1c in the hepatocyte nuclear fraction. In addition, the mRNA expression of SREBP-1c-target lipogenic genes ACACA, FASN, and DGAT1 was greater in the liver of dairy cows with severe fatty liver. In vitro experiments were conducted on hepatocytes isolated from 5 healthy 1-d-old female Holstein calves, and hepatocytes from each calf were run independently. First, hepatocytes were treated with 0, 200, or 400 μM palmitic acid (PA) for 12 h. Exogenous PA treatment decreased INSIG1 protein abundance, enhanced the endoplasmic reticulum to Golgi export of SCAP-precursor SREBP-1c complex and the nuclear translocation of mature SREBP-1c, all of which was associated with increased transcriptional activation of lipogenic genes and TG synthesis. Second, hepatocytes were transfected with INSIG1-overexpressing adenovirus for 48 h and treated with 400 μM PA 12 h before the end of transfection. Overexpressing INSIG1 inhibited PA-induced SREBP-1c processing, upregulation of lipogenic genes, and TG synthesis in hepatocytes. Overall, the present in vivo and in vitro results indicated that the low abundance of INSIG1 contributed to SREBP-1c processing and hepatic steatosis in dairy cows. Thus, the INSIG1-SCAP-SREBP-1c axis may be a novel target for treatment of fatty liver in dairy cows.
Topics: Cattle; Animals; Female; Sterol Regulatory Element Binding Protein 1; Fatty Acids, Nonesterified; 3-Hydroxybutyric Acid; Fatty Liver; Liver; Hepatocytes; Triglycerides; Insulin; RNA, Messenger; Glucose; Cattle Diseases
PubMed: 37291038
DOI: 10.3168/jds.2022-22895 -
The Biochemical Journal Dec 2023Atypical protein kinase Cs (aPKCs) are part of the PKC family of protein kinases and are atypical because they don't respond to the canonical PKC activators...
Atypical protein kinase Cs (aPKCs) are part of the PKC family of protein kinases and are atypical because they don't respond to the canonical PKC activators diacylglycerol (DAG) and Ca2+. They are central to the organization of polarized cells and are deregulated in several cancers. aPKC recruitment to the plasma membrane compartment is crucial to their encounter with substrates associated with polarizing functions. However, in contrast with other PKCs, the mechanism by which atypical PKCs are recruited there has remained elusive until recently. Here, we bring aPKC into the fold, summarizing recent reports on the direct recruitment of aPKC to membranes, providing insight into seemingly discrepant findings and integrating them with existing literature.
Topics: Protein Kinase C; Cell Membrane
PubMed: 38100320
DOI: 10.1042/BCJ20230390 -
BioRxiv : the Preprint Server For... Oct 2023Bacterial membranes are complex and dynamic, arising from an array of evolutionary pressures. One enzyme that alters membrane compositions through covalent lipid...
Bacterial membranes are complex and dynamic, arising from an array of evolutionary pressures. One enzyme that alters membrane compositions through covalent lipid modification is MprF. We recently identified that MprF synthesizes lysyl-phosphatidylglycerol (Lys-PG) from anionic PG, and a novel cationic lipid, lysyl-glucosyl-diacylglycerol (Lys-Glc-DAG), from neutral glycolipid Glc-DAG. This unexpected result prompted us to investigate whether Lys-Glc-DAG occurs in other MprF-containing bacteria, and whether other novel MprF products exist. Here, we studied protein sequence features determining MprF substrate specificity. First, pairwise analyses identified several streptococcal MprFs synthesizing Lys-Glc-DAG. Second, a restricted Boltzmann machine-guided approach led us to discover an entirely new substrate for MprF in , diglucosyl-diacylglycerol (Glc2-DAG), and an expanded set of organisms that modify glycolipid substrates using MprF. Overall, we combined the wealth of available sequence data with machine learning to model evolutionary constraints on MprF sequences across the bacterial domain, thereby identifying a novel cationic lipid.
PubMed: 37873101
DOI: 10.1101/2023.10.12.562061 -
Lipids in Health and Disease Apr 2024Pulmonary fibrosis (PF) is a severe pulmonary disease with limited available therapeutic choices. Recent evidence increasingly points to abnormal lipid metabolism as a... (Review)
Review
Pulmonary fibrosis (PF) is a severe pulmonary disease with limited available therapeutic choices. Recent evidence increasingly points to abnormal lipid metabolism as a critical factor in PF pathogenesis. Our latest research identifies the dysregulation of low-density lipoprotein (LDL) is a new risk factor for PF, contributing to alveolar epithelial and endothelial cell damage, and fibroblast activation. In this study, we first integrative summarize the published literature about lipid metabolite changes found in PF, including phospholipids, glycolipids, steroids, fatty acids, triglycerides, and lipoproteins. We then reanalyze two single-cell RNA-sequencing (scRNA-seq) datasets of PF, and the corresponding lipid metabolomic genes responsible for these lipids' biosynthesis, catabolism, transport, and modification processes are uncovered. Intriguingly, we found that macrophage is the most active cell type in lipid metabolism, with almost all lipid metabolic genes being altered in macrophages of PF. In type 2 alveolar epithelial cells, lipid metabolic differentially expressed genes (DEGs) are primarily associated with the cytidine diphosphate diacylglycerol pathway, cholesterol metabolism, and triglyceride synthesis. Endothelial cells are partly responsible for sphingomyelin, phosphatidylcholine, and phosphatidylethanolamines reprogramming as their metabolic genes are dysregulated in PF. Fibroblasts may contribute to abnormal cholesterol, phosphatidylcholine, and phosphatidylethanolamine metabolism in PF. Therefore, the reprogrammed lipid profiles in PF may be attributed to the aberrant expression of lipid metabolic genes in different cell types. Taken together, these insights underscore the potential of targeting lipid metabolism in developing innovative therapeutic strategies, potentially leading to extended overall survival in individuals affected by PF.
Topics: Humans; Pulmonary Fibrosis; Single-Cell Gene Expression Analysis; Lipid Metabolism; Endothelial Cells; Phospholipids; Cholesterol; Phosphatidylcholines
PubMed: 38570797
DOI: 10.1186/s12944-024-02062-8 -
IScience Jul 2023A sustainable and green approach was developed for the scalable synthesis of uncommon naturally occurring phospholipid species, Hemi-bis(monoacylglycero)phosphates...
A sustainable and green approach was developed for the scalable synthesis of uncommon naturally occurring phospholipid species, Hemi-bis(monoacylglycero)phosphates (Hemi-BMPs) and bis(diacylglycero)phosphates (BDPs) via the phospholipase D (PLD) mediated transphosphatidylation. PLD from . showed great substrate promiscuity for both phospholipids from different biological sources, and alcohol donors with diverse regiochemistry; monoacylglycerols with diverse fatty acyl structures (C12-C22), affording 74-92 wt% yields in 2 h. Experimental results demonstrated that the reaction rate is rather independent of phosphatidyls but to a large extent governed by the size, shape and regiolocation of fatty acyls incorporated on the glycerol backbone, particularly for the regio-isomers of bulky diacylglycerols (-1,3 or -1,2), which displays great diversity. In addition, a plausible mechanism is proposed based on molecular simulations for an elaborated explanation of the reaction thermodynamic and kinetic favorability toward the synthesis of Hemi-BMPs and BDPs.
PubMed: 37448559
DOI: 10.1016/j.isci.2023.107075