Tag: lipid metabolism

A Novel Fluorogenic Probe Reveals Lipid Droplet Dynamics in ME/CFS Fibroblasts

Abstract:

Lipid droplets (LDs) are dynamic cellular organelles that play an essential role in lipid metabolism and storage. LD dysregulation has been implicated in various diseases. However, investigations into the cellular LD dynamics under disease conditions have been rarely reported, possibly due to the absence of high performing LD imaging agents.

Here a novel fluorogenic probe, AM-QTPA, is reported for specific LD imaging. AM-QTPA demonstrates viscosity sensitivity and aggregation-induced emission enhancement characteristics. It is live cell permeable and can specifically light up LDs in cells, with low background noise and superior signals that can be quantified.

After validation in cell model with LD accumulation induced by oleic acid treatment, AM-QTPA is applied in a small proof-of-concept number of human fibroblast samples derived from people diagnosed with myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), a complex and debilitating disease with unknown cause.

The results indicate the presence of larger but fewer LDs in ME/CFS fibroblasts compared to the healthy counterparts, accompanying with frequent LD-mitochondria contacts, suggesting potential upregulation of lipolysis in ME/CFS connective tissue like fibroblasts.

Overall, AM-QTPA provides new understanding of the anomalous LD dynamics in disease status, which, potentially, will facilitate in-depth investigation of the pathogenesis of ME/CFS.

Source: Ding, S., Sanislav, O., Missailidis, D., Allan, C.Y., Owyong, T.C., Wu, M.-Y., Chen, S., Fisher, P.R., Annesley, S.J. and Hong, Y. (2024), A Novel Fluorogenic Probe Reveals Lipid Droplet Dynamics in ME/CFS Fibroblasts. Adv. Sensor Res. 2300178. https://doi.org/10.1002/adsr.202300178 https://onlinelibrary.wiley.com/doi/full/10.1002/adsr.202300178 (Full text)

Altered Lipid, Energy Metabolism and Oxidative Stress Are Common Features in a Range of Chronic Conditions

Abstract:

Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), Gulf War Syndrome (GWS) and Fibromyalgia are chronic illnesses that, despite their prevalence in society, are still of unknown aetiology. All three conditions present similar clinical symptoms and are difficult to diagnose due to a lack of appropriate biomarkers. Currently, diagnosis consists of satisfying clinical criteria and eliminating other conditions, a lengthy and often costly process for patients. The discovery of biomarkers would significantly speed up patient diagnosis and allow the development of pharmacological therapies that target the underlying metabolic causes of these diseases.

Metabolomics is an emerging research area used to characterise the metabolites present within biological specimens. Developments within this field now allow the analysis of thousands of metabolites within different samples and model systems, and have the potential to aid in unravelling the metabolic phenotypes that underpin complex metabolic diseases. ME/CFS, GWS and Fibromyalgia are three conditions that could benefit from a plasma/tissue metabolomics analysis, allowing a greater understanding of their aetiology and identify common pathways. An analysis of the literature in these conditions reveals alterations within pathways associated with energy and lipid metabolism with alterations in key metabolites associated with elevated oxidative stress. Understanding what might drive the elevated oxidative stress within all three illnesses will not only be important in future research but could also be a potential therapeutic target for antioxidant medications which could be implemented to reduce the symptom burden in these illnesses.

Source: MORTEN, Karl Jonathan and Davis, Leah and Lodge, Tiffany A. and Strong, James and Espejo-Oltra, José Andrés and Zalewski, Pawel and Pretorius, Etheresia, Altered Lipid, Energy Metabolism and Oxidative Stress Are Common Features in a Range of Chronic Conditions. Available at SSRN: https://ssrn.com/abstract=4455366 or http://dx.doi.org/10.2139/ssrn.4455366 (Full text available as PDF file)

Multiomic characterisation of the long-term sequelae of SARS survivors: a clinical observational study

Abstract:

Background: We aimed to characterise the long-term health outcomes of survivors of severe acute respiratory syndrome (SARS) and determine their recovery status and possible immunological basis.

Methods: We performed a clinical observational study on 14 health workers who survived SARS coronavirus infection between Apr 20, 2003 and Jun 6, 2003 in Haihe Hospital (Tianjin, China). Eighteen years after discharge, SARS survivors were interviewed using questionnaires on symptoms and quality of life, and received physical examination, laboratory tests, pulmonary function tests, arterial blood gas analysis, and chest imaging. Plasma samples were collected for metabolomic, proteomic, and single-cell transcriptomic analyses. The health outcomes were compared 18 and 12 years after discharge. Control individuals were also health workers from the same hospital but did not infect with SARS coronavirus.

Findings: Fatigue was the most common symptom in SARS survivors 18 years after discharge, with osteoporosis and necrosis of the femoral head being the main sequelae. The respiratory function and hip function scores of the SARS survivors were significantly lower than those of the controls. Physical and social functioning at 18 years was improved compared to that after 12 years but still worse than the controls. Emotional and mental health were fully recovered. Lung lesions on CT scans remained consistent at 18 years, especially in the right upper lobe and left lower lobe lesions. Plasma multiomics analysis indicated an abnormal metabolism of amino acids and lipids, promoted host defense immune responses to bacteria and external stimuli, B-cell activation, and enhanced cytotoxicity of CD8+ T cells but impaired antigen presentation capacity of CD4+ T cells.

Interpretation: Although health outcomes continued to improve, our study suggested that SARS survivors still suffered from physical fatigue, osteoporosis, and necrosis of the femoral head 18 years after discharge, possibly related to plasma metabolic disorders and immunological alterations.

Funding: This study was funded by the Tianjin Haihe Hospital Science and Technology Fund (HHYY-202012) and Tianjin Key Medical Discipline (Specialty) Construction Project (TJYXZDXK-063B, TJYXZDXK-067C).

Source: Li K, Wu Q, Li H, Sun H, Xing Z, Li L, Chen H. Multiomic characterisation of the long-term sequelae of SARS survivors: a clinical observational study. EClinicalMedicine. 2023 Apr;58:101884. doi: 10.1016/j.eclinm.2023.101884. Epub 2023 Feb 27. PMID: 36873427; PMCID: PMC9969173.

Developing a blood cell-based diagnostic test for myalgic encephalomyelitis/chronic fatigue syndrome using peripheral blood mononuclear cells

Abstract:

A blood-based diagnostic test for myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) and multiple sclerosis (MS) would be of great value in both conditions, facilitating more accurate and earlier diagnosis, helping with current treatment delivery, and supporting the development of new therapeutics.

Here we use Raman micro-spectroscopy to examine differences between the spectral profiles of blood cells of ME/CFS, MS and healthy controls.

We were able to discriminate the three groups using ensemble classification models with high levels of accuracy (91%) with the additional ability to distinguish mild, moderate, and severe ME/CFS patients from each other (84%).

To our knowledge, this is the first research using Raman micro-spectroscopy to discriminate specific subgroups of ME/CFS patients on the basis of their symptom severity. Specific Raman peaks linked with the different disease types with the potential in further investigations to provide insights into biological changes associated with the different conditions.

Source: Jiabao Xu, Tiffany Lodge,  Caroline Claire Kingdon, James W L Strong, John Maclennan, Eliana Lacerda, Slawomir Kujawski, Pawel Zalewski, Wei Huang, Karl J. Morten. Developing a blood cell-based diagnostic test for myalgic encephalomyelitis/chronic fatigue syndrome using peripheral blood mononuclear cells. medRxiv [Preprint] medRxiv 2023.03.18.23286575; doi: https://doi.org/10.1101/2023.03.18.23286575 https://www.medrxiv.org/content/10.1101/2023.03.18.23286575v1.full-text (Full text)

A global lipid map reveals host dependency factors conserved across SARS-CoV-2 variants

Abstract:

A comprehensive understanding of host dependency factors for SARS-CoV-2 remains elusive. Here, we map alterations in host lipids following SARS-CoV-2 infection using nontargeted lipidomics. We find that SARS-CoV-2 rewires host lipid metabolism, significantly altering hundreds of lipid species to effectively establish infection. We correlate these changes with viral protein activity by transfecting human cells with each viral protein and performing lipidomics.

We find that lipid droplet plasticity is a key feature of infection and that viral propagation can be blocked by small-molecule glycerolipid biosynthesis inhibitors. We find that this inhibition was effective against the main variants of concern (alpha, beta, gamma, and delta), indicating that glycerolipid biosynthesis is a conserved host dependency factor that supports this evolving virus.

Source: Farley SE, Kyle JE, Leier HC, Bramer LM, Weinstein JB, Bates TA, Lee JY, Metz TO, Schultz C, Tafesse FG. A global lipid map reveals host dependency factors conserved across SARS-CoV-2 variants. Nat Commun. 2022 Jun 17;13(1):3487. doi: 10.1038/s41467-022-31097-7. PMID: 35715395; PMCID: PMC9203258. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9203258/ (Full text)

Obesity and lipid metabolism disorders determine the risk for development of long COVID syndrome: a cross-sectional study from 50,402 COVID-19 patients

Abstract:

Purpose: Metabolic disorders have been identified as major risk factors for severe acute courses of COVID-19. With decreasing numbers of infections in many countries, the long COVID syndrome (LCS) represents the next major challenge in pandemic management, warranting the precise definition of risk factors for LCS development.

Methods: We identified 50,402 COVID-19 patients in the Disease Analyzer database (IQVIA) featuring data from 1056 general practices in Germany. Multivariate logistic regression analysis was used to identify risk factors for the development of LCS.

Results: Of the 50,402 COVID-19 patients included into this analysis, 1,708 (3.4%) were diagnosed with LCS. In a multivariate regression analysis, we identified lipid metabolism disorders (OR 1.46, 95% CI 1.28-1.65, p < 0.001) and obesity (OR 1.25, 95% CI 1.08-1.44, p = 0.003) as strong risk factors for the development of LCS. Besides these metabolic factors, patients’ age between 46 and 60 years (compared to age ≤ 30, (OR 1.81 95% CI 1.54-2.13, p < 0.001), female sex (OR 1.33, 95% CI 1.20-1.47, p < 0.001) as well as pre-existing asthma (OR 1.67, 95% CI 1.39-2.00, p < 0.001) and depression (OR 1.27, 95% CI 1.09-1.47, p = < 0.002) in women, and cancer (OR 1.4, 95% CI 1.09-1.95, p = < 0.012) in men were associated with an increased likelihood of developing LCS.

Conclusion: Lipid metabolism disorders and obesity represent age-independent risk factors for the development of LCS, suggesting that metabolic alterations determine the risk for unfavorable disease courses along all phases of COVID-19.

Source: Loosen SH, Jensen BO, Tanislav C, Luedde T, Roderburg C, Kostev K. Obesity and lipid metabolism disorders determine the risk for development of long COVID syndrome: a cross-sectional study from 50,402 COVID-19 patients. Infection. 2022 Mar 30:1–6. doi: 10.1007/s15010-022-01784-0. Epub ahead of print. PMID: 35355237; PMCID: PMC8966865. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8966865/ (Full text)

Sex-specific plasma lipid profiles of ME/CFS patients and their association with pain, fatigue, and cognitive symptoms

Abstract:

Background: Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a complex illness which disproportionally affects females. This illness is associated with immune and metabolic perturbations that may be influenced by lipid metabolism. We therefore hypothesized that plasma lipids from ME/CFS patients will provide a unique biomarker signature of disturbances in immune, inflammation and metabolic processes associated with ME/CFS.

Methods: Lipidomic analyses were performed on plasma from a cohort of 50 ME/CFS patients and 50 controls (50% males and similar age and ethnicity per group). Analyses were conducted with nano-flow liquid chromatography (nLC) and high-performance liquid chromatography (HPLC) systems coupled with a high mass accuracy ORBITRAP mass spectrometer, allowing detection of plasma lipid concentration ranges over three orders of magnitude. We examined plasma phospholipids (PL), neutral lipids (NL) and bioactive lipids in ME/CFS patients and controls and examined the influence of sex on the relationship between lipids and ME/CFS diagnosis.

Results: Among females, levels of total phosphatidylethanolamine (PE), omega-6 arachidonic acid-containing PE, and total hexosylceramides (HexCer) were significantly decreased in ME/CFS compared to controls. In males, levels of total HexCer, monounsaturated PE, phosphatidylinositol (PI), and saturated triglycerides (TG) were increased in ME/CFS patients compared to controls. Additionally, omega-6 linoleic acid-derived oxylipins were significantly increased in male ME/CFS patients versus male controls. Principal component analysis (PCA) identified three major components containing mostly PC and a few PE, PI and SM species-all of which were negatively associated with headache and fatigue severity, irrespective of sex. Correlations of oxylipins, ethanolamides and ME/CFS symptom severity showed that lower concentrations of these lipids corresponded with an increase in the severity of headaches, fatigue and cognitive difficulties and that this association was influenced by sex.

Conclusion: The observed sex-specific pattern of dysregulated PL, NL, HexCer and oxylipins in ME/CFS patients suggests a possible role of these lipids in promoting immune dysfunction and inflammation which may be among the underlying factors driving the clinical presentation of fatigue, chronic pain, and cognitive difficulties in ill patients. Further evaluation of lipid metabolism pathways is warranted to better understand ME/CFS pathogenesis.

Source: Nkiliza A, Parks M, Cseresznye A, Oberlin S, Evans JE, Darcey T, Aenlle K, Niedospial D, Mullan M, Crawford F, Klimas N, Abdullah L. Sex-specific plasma lipid profiles of ME/CFS patients and their association with pain, fatigue, and cognitive symptoms. J Transl Med. 2021 Aug 28;19(1):370. doi: 10.1186/s12967-021-03035-6. PMID: 34454515. https://pubmed.ncbi.nlm.nih.gov/34454515/

A map of metabolic phenotypes in patients with myalgic encephalomyelitis/chronic fatigue syndrome

Abstract:

Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a debilitating disease usually presenting after infection. Emerging evidence supports that energy metabolism is affected in ME/CFS, but a unifying metabolic phenotype has not been firmly established. We performed global metabolomics, lipidomics, and hormone measurements, and we used exploratory data analyses to compare serum from 83 patients with ME/CFS and 35 healthy controls.

Some changes were common in the patient group, and these were compatible with effects of elevated energy strain and altered utilization of fatty acids and amino acids as catabolic fuels. In addition, a set of heterogeneous effects reflected specific changes in 3 subsets of patients, and 2 of these expressed characteristic contexts of deregulated energy metabolism. The biological relevance of these metabolic phenotypes (metabotypes) was supported by clinical data and independent blood analyses.

In summary, we report a map of common and context-dependent metabolic changes in ME/CFS, and some of them presented possible associations with clinical patient profiles. We suggest that elevated energy strain may result from exertion-triggered tissue hypoxia and lead to systemic metabolic adaptation and compensation. Through various mechanisms, such metabolic dysfunction represents a likely mediator of key symptoms in ME/CFS and possibly a target for supportive intervention.

Source: Hoel F, Hoel A, Pettersen IK, Rekeland IG, Risa K, Alme K, Sørland K, Fosså A, Lien K, Herder I, Thürmer HL, Gotaas ME, Schäfer C, Berge RK, Sommerfelt K, Marti HP, Dahl O, Mella O, Fluge Ø, Tronstad KJ. A map of metabolic phenotypes in patients with myalgic encephalomyelitis/chronic fatigue syndrome. JCI Insight. 2021 Aug 23;6(16):149217. doi: 10.1172/jci.insight.149217. PMID: 34423789. https://pubmed.ncbi.nlm.nih.gov/34423789/

Exercise modifies glutamate and other metabolic biomarkers in cerebrospinal fluid from Gulf War Illness and Myalgic encephalomyelitis / Chronic Fatigue Syndrome

Abstract:

Myalgic encephalomyelitis / Chronic Fatigue Syndrome (ME/CFS) and Gulf War Illness (GWI) share many symptoms of fatigue, pain, and cognitive dysfunction that are not relieved by rest. Patterns of serum metabolites in ME/CFS and GWI are different from control groups and suggest potential dysfunction of energy and lipid metabolism. The metabolomics of cerebrospinal fluid was contrasted between ME/CFS, GWI and sedentary controls in 2 sets of subjects who had lumbar punctures after either (a) rest or (b) submaximal exercise stress tests. Postexercise GWI and control subjects were subdivided according to acquired transient postexertional postural tachycardia. Banked cerebrospinal fluid specimens were assayed using Biocrates AbsoluteIDQ® p180 kits for quantitative targeted metabolomics studies of amino acids, amines, acylcarnitines, sphingolipids, lysophospholipids, alkyl and ether phosphocholines.

Glutamate was significantly higher in the subgroup of postexercise GWI subjects who did not develop postural tachycardia after exercise compared to nonexercise and other postexercise groups. The only difference between nonexercise groups was higher lysoPC a C28:0 in GWI than ME/CFS suggesting this biochemical or phospholipase activities may have potential as a biomarker to distinguish between the 2 diseases. Exercise effects were suggested by elevation of short chain acylcarnitine C5-OH (C3-DC-M) in postexercise controls compared to nonexercise ME/CFS. Limitations include small subgroup sample sizes and absence of postexercise ME/CFS specimens. Mechanisms of glutamate neuroexcitotoxicity may contribute to neuropathology and “neuroinflammation” in the GWI subset who did not develop postural tachycardia after exercise. Dysfunctional lipid metabolism may distinguish the predominantly female ME/CFS group from predominantly male GWI subjects.

Source: Baraniuk JN, Kern G, Narayan V, Cheema A. Exercise modifies glutamate and other metabolic biomarkers in cerebrospinal fluid from Gulf War Illness and Myalgic encephalomyelitis / Chronic Fatigue Syndrome. PLoS One. 2021 Jan 13;16(1):e0244116. doi: 10.1371/journal.pone.0244116. PMID: 33440400. https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0244116 (Full text)

Comprehensive Circulatory Metabolomics in ME/CFS Reveals Disrupted Metabolism of Acyl Lipids and Steroids

Abstract:

The latest worldwide prevalence rate projects that over 65 million patients suffer from myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), an illness with known effects on the functioning of the immune and nervous systems. We performed an extensive metabolomics analysis on the plasma of 52 female subjects, equally sampled between controls and ME/CFS patients, which delivered data for about 1750 blood compounds spanning 20 super-pathways, subdivided into 113 sub-pathways.

Statistical analysis combined with pathway enrichment analysis points to a few disrupted metabolic pathways containing many unexplored compounds. The most intriguing finding concerns acyl cholines, belonging to the fatty acid metabolism sub-pathway of lipids, for which all compounds are consistently reduced in two distinct ME/CFS patient cohorts. We compiled the extremely limited knowledge about these compounds and regard them as promising in the quest to explain many of the ME/CFS symptoms.

Another class of lipids with far-reaching activity on virtually all organ systems are steroids; androgenic, progestin, and corticosteroids are broadly reduced in our patient cohort. We also report on lower dipeptides and elevated sphingolipids abundance in patients compared to controls. Disturbances in the metabolism of many of these molecules can be linked to the profound organ system symptoms endured by ME/CFS patients.

Source: Germain A, Barupal DK, Levine SM, Hanson MR. Comprehensive Circulatory Metabolomics in ME/CFS Reveals Disrupted Metabolism of Acyl Lipids and Steroids. Metabolites. 2020 Jan 14;10(1). pii: E34. doi: 10.3390/metabo10010034. https://www.ncbi.nlm.nih.gov/pubmed/31947545