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Gastroenterology Jun 2023Alcohol disturbs hepatic lipid synthesis and transport, but the role of lipid dysfunction in alcohol-related liver disease (ALD) is unclear. In this biopsy-controlled,... (Observational Study)
Observational Study
BACKGROUND & AIMS
Alcohol disturbs hepatic lipid synthesis and transport, but the role of lipid dysfunction in alcohol-related liver disease (ALD) is unclear. In this biopsy-controlled, prospective, observational study, we characterized the liver and plasma lipidomes in patients with early ALD.
METHODS
We performed mass spectrometry-based lipidomics of paired liver and plasma samples from 315 patients with ALD and of plasma from 51 matched healthy controls. We associated lipid levels with histologic fibrosis, inflammation, and steatosis with correction for multiple testing and adjustment for confounders. We further investigated sphingolipid regulation by means of quantitative real-time polymerase chain reaction sequencing of microRNA, prediction of liver-related events, and tested causality with Mendelian randomization.
RESULTS
We detected 198 lipids in the liver and 236 lipids in the circulation from 18 lipid classes. Most sphingolipids (sphingomyelins and ceramides) and phosphocholines were co-down-regulated in both liver and plasma, where lower abundance correlated with higher fibrosis stage. Sphingomyelins showed the most pronounced negative correlation to fibrosis, mirrored by negative correlations in both liver and plasma with hepatic inflammation. Reduced sphingomyelins predicted future liver-related events. This seemed to be characteristic of "pure ALD," as sphingomyelin levels were higher in patients with concomitant metabolic syndrome and ALD/nonalcoholic fatty liver disease overlap. Mendelian randomization in FinnGen and UK Biobanks indicated ALD as the cause of low sphingomyelins, and alcohol use disorder did not correlate with genetic susceptibility to low sphingomyelin levels.
CONCLUSIONS
Alcohol-related liver fibrosis is characterized by selective and progressive lipid depletion in liver and blood, particularly sphingomyelins, which also associates with progression to liver-related events.
Topics: Humans; Sphingolipids; Sphingomyelins; Prospective Studies; Liver Cirrhosis; Liver; Ethanol; Non-alcoholic Fatty Liver Disease; Fibrosis; Inflammation
PubMed: 36849086
DOI: 10.1053/j.gastro.2023.02.023 -
Cell Metabolism Aug 2020The coronavirus disease 2019 (COVID-19) pandemic presents an unprecedented threat to global public health. Herein, we utilized a combination of targeted and untargeted...
The coronavirus disease 2019 (COVID-19) pandemic presents an unprecedented threat to global public health. Herein, we utilized a combination of targeted and untargeted tandem mass spectrometry to analyze the plasma lipidome and metabolome in mild, moderate, and severe COVID-19 patients and healthy controls. A panel of 10 plasma metabolites effectively distinguished COVID-19 patients from healthy controls (AUC = 0.975). Plasma lipidome of COVID-19 resembled that of monosialodihexosyl ganglioside (GM3)-enriched exosomes, with enhanced levels of sphingomyelins (SMs) and GM3s, and reduced diacylglycerols (DAGs). Systems evaluation of metabolic dysregulation in COVID-19 was performed using multiscale embedded differential correlation network analyses. Using exosomes isolated from the same cohort, we demonstrated that exosomes of COVID-19 patients with elevating disease severity were increasingly enriched in GM3s. Our work suggests that GM3-enriched exosomes may partake in pathological processes related to COVID-19 pathogenesis and presents the largest repository on the plasma lipidome and metabolome distinct to COVID-19.
Topics: Adult; Aged; Betacoronavirus; CD4-Positive T-Lymphocytes; COVID-19; Coronavirus Infections; Diglycerides; Exosomes; Female; G(M3) Ganglioside; Gangliosides; Humans; Male; Metabolome; Metabolomics; Middle Aged; Pandemics; Pneumonia, Viral; SARS-CoV-2; Sphingomyelins; Tandem Mass Spectrometry; Young Adult
PubMed: 32610096
DOI: 10.1016/j.cmet.2020.06.016 -
Nature Communications Jan 2022Pancreatic cancer has the worst prognosis among all cancers. Cancer screening of body fluids may improve the survival time prognosis of patients, who are often diagnosed...
Pancreatic cancer has the worst prognosis among all cancers. Cancer screening of body fluids may improve the survival time prognosis of patients, who are often diagnosed too late at an incurable stage. Several studies report the dysregulation of lipid metabolism in tumor cells, suggesting that changes in the blood lipidome may accompany tumor growth. Here we show that the comprehensive mass spectrometric determination of a wide range of serum lipids reveals statistically significant differences between pancreatic cancer patients and healthy controls, as visualized by multivariate data analysis. Three phases of biomarker discovery research (discovery, qualification, and verification) are applied for 830 samples in total, which shows the dysregulation of some very long chain sphingomyelins, ceramides, and (lyso)phosphatidylcholines. The sensitivity and specificity to diagnose pancreatic cancer are over 90%, which outperforms CA 19-9, especially at an early stage, and is comparable to established diagnostic imaging methods. Furthermore, selected lipid species indicate a potential as prognostic biomarkers.
Topics: Biomarkers, Tumor; CA-19-9 Antigen; Case-Control Studies; Ceramides; Female; Humans; Lipid Metabolism; Lipidomics; Lysophosphatidylcholines; Male; Multivariate Analysis; Pancreatic Neoplasms; Proportional Hazards Models; Sensitivity and Specificity; Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization; Sphingomyelins
PubMed: 35013261
DOI: 10.1038/s41467-021-27765-9 -
Brain : a Journal of Neurology Oct 2022Many genetic risk factors for Parkinson's disease have lipid-related functions and lipid-modulating drugs such as statins may be protective against Parkinson's disease....
Many genetic risk factors for Parkinson's disease have lipid-related functions and lipid-modulating drugs such as statins may be protective against Parkinson's disease. Moreover, the hallmark Parkinson's disease pathological protein, α-synuclein, has lipid membrane function and pathways dysregulated in Parkinson's disease such as the endosome-lysosome system and synaptic signalling rely heavily on lipid dynamics. Despite the potential role for lipids in Parkinson's disease, most research to date has been protein-centric, with large-scale, untargeted serum and CSF lipidomic comparisons between genetic and idiopathic Parkinson's disease and neurotypical controls limited. In particular, the extent to which lipid dysregulation occurs in mutation carriers of one of the most common Parkinson's disease risk genes, LRRK2, is unclear. Further, the functional lipid pathways potentially dysregulated in idiopathic and LRRK2 mutation Parkinson's disease are underexplored. To better determine the extent of lipid dysregulation in Parkinson's disease, untargeted high-performance liquid chromatography-tandem mass spectrometry was performed on serum (n = 221) and CSF (n = 88) obtained from a multi-ethnic population from the Michael J. Fox Foundation LRRK2 Clinical Cohort Consortium. The cohort consisted of controls, asymptomatic LRRK2 G2019S carriers, LRRK2 G2019S carriers with Parkinson's disease and Parkinson's disease patients without a LRRK2 mutation. Age and sex were adjusted for in analyses where appropriate. Approximately 1000 serum lipid species per participant were analysed. The main serum lipids that distinguished both Parkinson's disease patients and LRRK2 mutation carriers from controls included species of ceramide, triacylglycerol, sphingomyelin, acylcarnitine, phosphatidylcholine and lysophosphatidylethanolamine. Significant alterations in sphingolipids and glycerolipids were also reflected in Parkinson's disease and LRRK2 mutation carrier CSF, although no correlations were observed between lipids identified in both serum and CSF. Pathway analysis of altered lipid species indicated that sphingolipid metabolism, insulin signalling and mitochondrial function were the major metabolic pathways dysregulated in Parkinson's disease. Importantly, these pathways were also found to be dysregulated in serum samples from a second Parkinson's disease cohort (n = 315). Results from this study demonstrate that dysregulated lipids in Parkinson's disease generally, and in LRRK2 mutation carriers, are from functionally and metabolically related pathways. These findings provide new insight into the extent of lipid dysfunction in Parkinson's disease and therapeutics manipulating these pathways may be beneficial for Parkinson's disease patients. Moreover, serum lipid profiles may be novel biomarkers for both genetic and idiopathic Parkinson's disease.
Topics: Humans; Parkinson Disease; alpha-Synuclein; Leucine-Rich Repeat Serine-Threonine Protein Kinase-2; Sphingomyelins; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Biomarkers; Ceramides; Phosphatidylcholines; Triglycerides; Insulins
PubMed: 35551349
DOI: 10.1093/brain/awac176 -
Communications Biology Oct 2022Dysregulation of sphingomyelin and ceramide metabolism have been implicated in Alzheimer's disease. Genome-wide and transcriptome-wide association studies have...
Dysregulation of sphingomyelin and ceramide metabolism have been implicated in Alzheimer's disease. Genome-wide and transcriptome-wide association studies have identified various genes and genetic variants in lipid metabolism that are associated with Alzheimer's disease. However, the molecular mechanisms of sphingomyelin and ceramide disruption remain to be determined. We focus on the sphingolipid pathway and carry out multi-omics analyses to identify central and peripheral metabolic changes in Alzheimer's patients, correlating them to imaging features. Our multi-omics approach is based on (a) 2114 human post-mortem brain transcriptomics to identify differentially expressed genes; (b) in silico metabolic flux analysis on context-specific metabolic networks identified differential reaction fluxes; (c) multimodal neuroimaging analysis on 1576 participants to associate genetic variants in sphingomyelin pathway with Alzheimer's disease pathogenesis; (d) plasma metabolomic and lipidomic analysis to identify associations of lipid species with dysregulation in Alzheimer's; and (e) metabolite genome-wide association studies to define receptors within the pathway as a potential drug target. We validate our hypothesis in amyloidogenic APP/PS1 mice and show prolonged exposure to fingolimod alleviated synaptic plasticity and cognitive impairment in mice. Our integrative multi-omics approach identifies potential targets in the sphingomyelin pathway and suggests modulators of S1P metabolism as possible candidates for Alzheimer's disease treatment.
Topics: Alzheimer Disease; Animals; Ceramides; Fingolimod Hydrochloride; Genome-Wide Association Study; Humans; Mice; Sphingolipids; Sphingomyelins
PubMed: 36209301
DOI: 10.1038/s42003-022-04011-6 -
Cell Reports Nov 2021The highly lethal brain cancer glioblastoma (GBM) poses a daunting challenge because the blood-brain barrier renders potentially druggable amplified or mutated...
The highly lethal brain cancer glioblastoma (GBM) poses a daunting challenge because the blood-brain barrier renders potentially druggable amplified or mutated oncoproteins relatively inaccessible. Here, we identify sphingomyelin phosphodiesterase 1 (SMPD1), an enzyme that regulates the conversion of sphingomyelin to ceramide, as an actionable drug target in GBM. We show that the highly brain-penetrant antidepressant fluoxetine potently inhibits SMPD1 activity, killing GBMs, through inhibition of epidermal growth factor receptor (EGFR) signaling and via activation of lysosomal stress. Combining fluoxetine with temozolomide, a standard of care for GBM, causes massive increases in GBM cell death and complete tumor regression in mice. Incorporation of real-world evidence from electronic medical records from insurance databases reveals significantly increased survival in GBM patients treated with fluoxetine, which was not seen in patients treated with other selective serotonin reuptake inhibitor (SSRI) antidepressants. These results nominate the repurposing of fluoxetine as a potentially safe and promising therapy for patients with GBM and suggest prospective randomized clinical trials.
Topics: Animals; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Blood-Brain Barrier; Brain Neoplasms; Cell Line, Tumor; Drug Repositioning; Electronic Health Records; Energy Metabolism; ErbB Receptors; Female; Fluoxetine; Glioblastoma; Humans; Mice, Nude; Permeability; Retrospective Studies; Signal Transduction; Sphingomyelin Phosphodiesterase; Sphingomyelins; Temozolomide; Tumor Burden; Tumor Cells, Cultured; Xenograft Model Antitumor Assays; Mice
PubMed: 34731610
DOI: 10.1016/j.celrep.2021.109957 -
JAMA Network Open Nov 2023Sphingolipids, including ceramides and sphingomyelins, may influence the pathophysiology and risk of sudden cardiac death (SCD) through multiple biological activities....
IMPORTANCE
Sphingolipids, including ceramides and sphingomyelins, may influence the pathophysiology and risk of sudden cardiac death (SCD) through multiple biological activities. Whether the length of the fatty acid acylated to plasma sphingolipid species is associated with SCD risk is not known.
OBJECTIVE
To determine whether the saturated fatty acid length of plasma ceramides and sphingomyelins influences the association with SCD risk.
DESIGN, SETTING, AND PARTICIPANTS
In this cohort study, multivariable Cox proportional hazards regression models were used to examine the association of sphingolipid species with SCD risk. The study population included 4612 participants in the Cardiovascular Health Study followed up prospectively for a median of 10.2 (IQR, 5.5-11.6) years. Baseline data were collected from January 1992 to December 1995 during annual examinations. Data were analyzed from February 11, 2020, to September 9, 2023.
EXPOSURES
Eight plasma sphingolipid species (4 ceramides and 4 sphingomyelins) with saturated fatty acids of 16, 20, 22, and 24 carbons.
MAIN OUTCOME AND MEASURE
Association of plasma ceramides and sphingomyelins with saturated fatty acids of different lengths with SCD risk.
RESULTS
Among the 4612 CHS participants included in the analysis (mean [SD] age, 77 [5] years; 2724 [59.1%] women; 6 [0.1%] American Indian; 4 [0.1%] Asian; 718 [15.6%] Black; 3869 [83.9%] White, and 15 [0.3%] Other), 215 SCD cases were identified. In adjusted Cox proportional hazards regression analyses, plasma ceramides and sphingomyelins with palmitic acid (Cer-16 and SM-16) were associated with higher SCD risk per higher SD of log sphingolipid levels (hazard ratio [HR] for Cer-16, 1.34 [95% CI, 1.12-1.59]; HR for SM-16, 1.37 [95% CI, 1.12-1.67]). Associations did not differ by baseline age, sex, race, or body mass index. No significant association of SCD with sphingolipids with very-long-chain saturated fatty acids was observed after correction for multiple testing (HR for ceramide with arachidic acid, 1.06 [95% CI, 0.90-1.24]; HR for ceramide with behenic acid, 0.92 [95% CI, 0.77-1.10]; HR for ceramide with lignoceric acid, 0.92 [95% CI, 0.77-1.09]; HR for sphingomyelin with arachidic acid, 0.83 [95% CI, 0.71-0.98]; HR for sphingomyelin with behenic acid, 0.84 [95% CI, 0.70-1.00]; HR for sphingomyelin with lignoceric acid, 0.86 [95% CI, 0.72-1.03]).
CONCLUSIONS AND RELEVANCE
The findings of this large, population-based cohort study of SCD identified that higher plasma levels of Cer-16 and SM-16 were associated with higher risk of SCD. Future studies are needed to examine the underlying mechanism of these associations.
Topics: Humans; Female; Aged; Male; Sphingomyelins; Ceramides; Eicosanoic Acids; Cohort Studies; Fatty Acids; Sphingolipids; Death, Sudden, Cardiac
PubMed: 37976059
DOI: 10.1001/jamanetworkopen.2023.43854 -
Biomolecules Oct 2020Sphingolipids (SLs) are critical components of membrane bilayers that play a crucial role in their physico-chemical properties. Ceramide is the prototype and most... (Review)
Review
Sphingolipids (SLs) are critical components of membrane bilayers that play a crucial role in their physico-chemical properties. Ceramide is the prototype and most studied SL due to its role as a second messenger in the regulation of multiple signaling pathways and cellular processes. Ceramide is a heterogeneous lipid entity determined by the length of the fatty acyl chain linked to its carbon backbone sphingosine, which can be generated either by de novo synthesis from serine and palmitoyl-CoA in the endoplasmic reticulum or via sphingomyelin (SM) hydrolysis by sphingomyelinases (SMases). Unlike de novo synthesis, SMase-induced SM hydrolysis represents a rapid and transient mechanism of ceramide generation in specific intracellular sites that accounts for the diverse biological effects of ceramide. Several SMases have been described at the molecular level, which exhibit different pH requirements for activity: neutral, acid or alkaline. Among the SMases, the neutral (NSMase) and acid (ASMase) are the best characterized for their contribution to signaling pathways and role in diverse pathologies, including liver diseases. As part of a Special Issue (Phospholipases: From Structure to Biological Function), the present invited review summarizes the physiological functions of NSMase and ASMase and their role in chronic and metabolic liver diseases, of which the most relevant is nonalcoholic steatohepatitis and its progression to hepatocellular carcinoma, due to the association with the obesity and type 2 diabetes epidemic. A better understanding of the regulation and role of SMases in liver pathology may offer the opportunity for novel treatments of liver diseases.
Topics: Ceramides; Diabetes Mellitus, Type 2; Humans; Liver; Liver Diseases; Signal Transduction; Sphingolipids; Sphingomyelin Phosphodiesterase; Sphingomyelins
PubMed: 33143193
DOI: 10.3390/biom10111497 -
Cells Oct 2021Autophagy is an evolutionarily conserved pathway, in which cytoplasmic components are sequestered within double-membrane vesicles called autophagosomes and then... (Review)
Review
Autophagy is an evolutionarily conserved pathway, in which cytoplasmic components are sequestered within double-membrane vesicles called autophagosomes and then transported into lysosomes or vacuoles for degradation. Over 40 conserved autophagy-related (ATG) genes define the core machinery for the five processes of autophagy: initiation, nucleation, elongation, closure, and fusion. In this review, we focus on one of the least well-characterized events in autophagy, namely the closure of the isolation membrane/phagophore to form the sealed autophagosome. This process is tightly regulated by ESCRT machinery, ATG proteins, Rab GTPase and Rab-related proteins, SNAREs, sphingomyelin, and calcium. We summarize recent progress in the regulation of autophagosome closure and discuss the key questions remaining to be addressed.
Topics: Animals; Autophagosomes; Calcium; Endosomal Sorting Complexes Required for Transport; Humans; SNARE Proteins; Sphingomyelins; rab GTP-Binding Proteins
PubMed: 34831036
DOI: 10.3390/cells10112814 -
Biochemical and Biophysical Research... Dec 2022Sphingomyelin has been considered as a merely structural lipid for many years. However, this organelle-specific lipid has many other roles, including increasing membrane... (Review)
Review
Sphingomyelin has been considered as a merely structural lipid for many years. However, this organelle-specific lipid has many other roles, including increasing membrane molecular order, acting as a source of ceramide in cell signaling and apoptosis, and forming clusters/nanodomains with cholesterol and ceramide. This contribution is dedicated to Professor E. Carafoli, on occasion of his 90th anniversary.
Topics: Sphingomyelins; Ceramides; Cholesterol; Apoptosis; Sphingomyelin Phosphodiesterase
PubMed: 36344153
DOI: 10.1016/j.bbrc.2022.08.074