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22 pages, 3375 KiB

Open AccessArticle

Mass Spectrometry-Based Lipidomics Reveals Differential Changes in the Accumulated Lipid Classes in Chronic Kidney Disease

by Lukasz Marczak, Jakub Idkowiak, Joanna Tracz, Maciej Stobiecki, Bartłomiej Perek, Katarzyna Kostka-Jeziorny, Andrzej Tykarski, Maria Wanic-Kossowska, Marcin Borowski, Marcin Osuch, Dorota Formanowicz and Magdalena Luczak

Metabolites 2021, 11(5), 275; https://0-doi-org.brum.beds.ac.uk/10.3390/metabo11050275 - 27 Apr 2021

Cited by 9 | Viewed by 3458

Abstract

Chronic kidney disease (CKD) is characterized by the progressive loss of functional nephrons. Although cardiovascular disease (CVD) complications and atherosclerosis are the leading causes of morbidity and mortality in CKD, the mechanism by which the progression of CVD accelerates remains unclear. To reveal [...] Read more.

Chronic kidney disease (CKD) is characterized by the progressive loss of functional nephrons. Although cardiovascular disease (CVD) complications and atherosclerosis are the leading causes of morbidity and mortality in CKD, the mechanism by which the progression of CVD accelerates remains unclear. To reveal the molecular mechanisms associated with atherosclerosis linked to CKD, we applied a shotgun lipidomics approach fortified with standard laboratory analytical methods and gas chromatography-mass spectrometry technique on selected lipid components and precursors to analyze the plasma lipidome in CKD and classical CVD patients. The MS-based lipidome profiling revealed the upregulation of triacylglycerols in CKD and downregulation of cholesterol/cholesteryl esters, sphingomyelins, phosphatidylcholines, phosphatidylethanolamines and ceramides as compared to CVD group and controls. We have further observed a decreased abundance of seven fatty acids in CKD with strong inter-correlation. In contrast, the level of glycerol was elevated in CKD in comparison to all analyzed groups. Our results revealed the putative existence of a functional causative link—the low cholesterol level correlated with lower estimated glomerular filtration rate and kidney dysfunction that supports the postulated “reverse epidemiology” theory and suggest that the lipidomic background of atherosclerosis-related to CKD is unique and might be associated with other cellular factors, i.e., inflammation. Full article

(This article belongs to the Special Issue Lipid and Lipoprotein Metabolism)

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11 pages, 805 KiB

Open AccessArticle

Metabolite Profile of Treatment-Naive Metabolic Syndrome Subjects in Relation to Cardiovascular Disease Risk

by Moritz V. Warmbrunn, Annefleur M. Koopen, Nicolien C. de Clercq, Pieter F. de Groot, Ruud S. Kootte, Kristien E. C. Bouter, Kasper W. ter Horst, Annick V. Hartstra, Mireille J. Serlie, Mariette T. Ackermans, Maarten R. Soeters, Daniel H. van Raalte, Mark Davids, Max Nieuwdorp and Albert K. Groen

Metabolites 2021, 11(4), 236; https://0-doi-org.brum.beds.ac.uk/10.3390/metabo11040236 - 13 Apr 2021

Cited by 4 | Viewed by 2241

Abstract

Metabolic syndrome (MetSyn) is an important risk factor for type 2 diabetes and cardiovascular diseases (CVD). This study aimed to find distinct plasma metabolite profiles between insulin-resistant and non-insulin resistant subjects with MetSyn and evaluate if MetSyn metabolite profiles are related to CVD [...] Read more.

Metabolic syndrome (MetSyn) is an important risk factor for type 2 diabetes and cardiovascular diseases (CVD). This study aimed to find distinct plasma metabolite profiles between insulin-resistant and non-insulin resistant subjects with MetSyn and evaluate if MetSyn metabolite profiles are related to CVD risk and lipid fluxes. In a cross-sectional study, untargeted metabolomics of treatment-naive males with MetSyn (n = 132) were analyzed together with clinical parameters. In a subset of MetSyn participants, CVD risk was calculated using the Framingham score (n = 111), and lipolysis (n = 39) was measured by a two-step hyperinsulinemic euglycemic clamp using [1,1,2,3,3-²H5] glycerol to calculate lipolysis suppression rates. Peripheral insulin resistance was related to fatty acid metabolism and glycerolphosphorylcholine. Interestingly, although insulin resistance is considered to be a risk factor for CVD, we observed that there was little correspondence between metabolites associated with insulin resistance and metabolites associated with CVD risk. The latter mainly belonged to the androgenic steroid, fatty acid, phosphatidylethanolamine, and phophatidylcholine pathways. These data provide new insights into metabolic changes in mild MetSyn pathophysiology and MetSyn CVD risk related to lipid metabolism. Prospective studies may focus on the pathophysiological role of the here-identified biomarkers. Full article

(This article belongs to the Special Issue Lipid and Lipoprotein Metabolism)

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13 pages, 314 KiB

Open AccessArticle

Association of Human Plasma Metabolomics with Delayed Dark Adaptation in Age-Related Macular Degeneration

by Kevin M. Mendez, Janice Kim, Inês Laíns, Archana Nigalye, Raviv Katz, Shrinivas Pundik, Ivana K. Kim, Liming Liang, Demetrios G. Vavvas, John B. Miller, Joan W. Miller, Jessica A. Lasky-Su and Deeba Husain

Metabolites 2021, 11(3), 183; https://0-doi-org.brum.beds.ac.uk/10.3390/metabo11030183 - 21 Mar 2021

Cited by 6 | Viewed by 2511

Abstract

The purpose of this study was to analyze the association between plasma metabolite levels and dark adaptation (DA) in age-related macular degeneration (AMD). This was a cross-sectional study including patients with AMD (early, intermediate, and late) and control subjects older than 50 years [...] Read more.

The purpose of this study was to analyze the association between plasma metabolite levels and dark adaptation (DA) in age-related macular degeneration (AMD). This was a cross-sectional study including patients with AMD (early, intermediate, and late) and control subjects older than 50 years without any vitreoretinal disease. Fasting blood samples were collected and used for metabolomic profiling with ultra-performance liquid chromatography–mass spectrometry (LC-MS). Patients were also tested with the AdaptDx (MacuLogix, Middletown, PA, USA) DA extended protocol (20 min). Two measures of dark adaptation were calculated and used: rod-intercept time (RIT) and area under the dark adaptation curve (AUDAC). Associations between dark adaption and metabolite levels were tested using multilevel mixed-effects linear modelling, adjusting for age, gender, body mass index (BMI), smoking, race, AMD stage, and Age-Related Eye Disease Study (AREDS) formulation supplementation. We included a total of 71 subjects: 53 with AMD (13 early AMD, 31 intermediate AMD, and 9 late AMD) and 18 controls. Our results revealed that fatty acid-related lipids and amino acids related to glutamate and leucine, isoleucine and valine metabolism were associated with RIT (p < 0.01). Similar results were found when AUDAC was used as the outcome. Fatty acid-related lipids and amino acids are associated with DA, thus suggesting that oxidative stress and mitochondrial dysfunction likely play a role in AMD and visual impairment in this condition. Full article

(This article belongs to the Special Issue Lipid and Lipoprotein Metabolism)

24 pages, 1593 KiB

Open AccessArticle

Collection and Storage of Human Plasma for Measurement of Oxylipins

by Kristen J. Polinski, Michael Armstrong, Jonathan Manke, Jennifer Seifert, Tessa Crume, Fan Yang, Michael Clare-Salzler, V. Michael Holers, Nichole Reisdorph and Jill M. Norris

Metabolites 2021, 11(3), 137; https://0-doi-org.brum.beds.ac.uk/10.3390/metabo11030137 - 26 Feb 2021

Cited by 10 | Viewed by 1967

Abstract

Oxylipins derived from omega-3 and -6 fatty acids are actively involved in inflammatory and immune processes and play important roles in human disease. However, as the interest in oxylipins increases, questions remain regarding which molecules are detectable in plasma, the best methods of [...] Read more.

Oxylipins derived from omega-3 and -6 fatty acids are actively involved in inflammatory and immune processes and play important roles in human disease. However, as the interest in oxylipins increases, questions remain regarding which molecules are detectable in plasma, the best methods of collecting samples, and if molecules are stable during collection and storage. We thereby built upon existing studies by examining the stability of an expanded panel of 90 oxylipins, including specialized pro-resolving lipid mediators (SPMs), in human plasma (n = 5 subjects) during sample collection, processing, and storage at −80 °C. Oxylipins were quantified using liquid chromatography-tandem mass spectrometry (LC/MS/MS). Blood samples collected in ethylenediaminetetraacetic acid (EDTA) or heparin followed by up to 2 h at room temperature prior to processing showed no significant differences in oxylipin concentrations compared to immediately processed samples, including the SPMs lipoxin A4 and resolvin D1. The majority of molecules, including SPMs, remained stable following storage for up to 1 year. However, in support of previous findings, changes were seen in a small subset of oxylipins including 12-HETE, TXB₂, 14-HDHA, and 18-HEPE. Overall, this study showed that accurate measurements of most oxylipins can be obtained from stored EDTA or heparin plasma samples using LC/MS/MS. Full article

(This article belongs to the Special Issue Lipid and Lipoprotein Metabolism)

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13 pages, 2019 KiB

Open AccessArticle

Chemical Labeling Assisted Detection and Identification of Short Chain Fatty Acid Esters of Hydroxy Fatty Acid in Rat Colon and Cecum Contents

by Siddabasave Gowda B. Gowda, Divyavani Gowda, Chongsheng Liang, Yonghan Li, Kentaro Kawakami, Satoru Fukiya, Atsushi Yokota, Hitoshi Chiba and Shu-Ping Hui

Metabolites 2020, 10(10), 398; https://0-doi-org.brum.beds.ac.uk/10.3390/metabo10100398 - 08 Oct 2020

Cited by 11 | Viewed by 3078

Abstract

Branched fatty acid esters of hydroxy fatty acids (FAHFAs) are novel endogenous lipids with important physiological functions in mammals. We previously identified a new type of FAHFAs, named short-chain fatty acid esterified hydroxy fatty acids (SFAHFAs), with acetyl or propyl esters of hydroxy [...] Read more.

Branched fatty acid esters of hydroxy fatty acids (FAHFAs) are novel endogenous lipids with important physiological functions in mammals. We previously identified a new type of FAHFAs, named short-chain fatty acid esterified hydroxy fatty acids (SFAHFAs), with acetyl or propyl esters of hydroxy fatty acids of carbon chains, C ≥ 20. However, sensitive determination of SFAHFAs is still a challenge, due to their high structural similarity and low abundance in biological samples. This study employs one-step chemical derivatization following total lipid extraction using 2-dimethylaminoethylamine (DMED) for enhanced detection of SFAHFAs. The labeled extracts were subjected to ultrahigh performance liquid chromatography coupled to linear ion trap quadrupole-Orbitrap mass spectrometry (UHPLC/LTQ-Orbitrap MS). Our results demonstrated that the detection sensitivities of SFAHFAs increased after DMED labeling, and is highly helpful in discovering six additional novel SFAHFAs in the cecum and colon contents of WKAH/HKmSlc rats fed with normal and high-fat diet (HFD). The identified DMED labeled SFAHFAs were characterized by their detailed MS/MS analysis, and their plausible fragmentation patterns were proposed. The concentrations of SFAHFAs were significantly reduced in the cecum of HFD group compared to the control. Hence, the proposed method could be a promising tool to apply for the enhanced detection of SFAHFAs in various biological matrices, which in turn facilitate the understanding of their sources, and physiological functions of these novel lipids. Full article

(This article belongs to the Special Issue Lipid and Lipoprotein Metabolism)

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17 pages, 2424 KiB

Open AccessArticle

Neuronal Lipoprotein Lipase Deficiency Alters Neuronal Function and Hepatic Metabolism

by Kimberley D. Bruce, Evgenia Dobrinskikh, Hong Wang, Ivan Rudenko, Hong Gao, Andrew E. Libby, Sachi Gorkhali, Tian Yu, Andrea Zsombok and Robert H. Eckel

Metabolites 2020, 10(10), 385; https://0-doi-org.brum.beds.ac.uk/10.3390/metabo10100385 - 28 Sep 2020

Cited by 6 | Viewed by 2628

Abstract

The autonomic regulation of hepatic metabolism offers a novel target for the treatment of non-alcoholic fatty liver disease (NAFLD). However, the molecular characteristics of neurons that regulate the brain-liver axis remain unclear. Since mice lacking neuronal lipoprotein lipase (LPL) develop perturbations in neuronal [...] Read more.

The autonomic regulation of hepatic metabolism offers a novel target for the treatment of non-alcoholic fatty liver disease (NAFLD). However, the molecular characteristics of neurons that regulate the brain-liver axis remain unclear. Since mice lacking neuronal lipoprotein lipase (LPL) develop perturbations in neuronal lipid-sensing and systemic energy balance, we reasoned that LPL might be a component of pre-autonomic neurons involved in the regulation of hepatic metabolism. Here, we show that, despite obesity, mice with reduced neuronal LPL (NEXCreLPL^flox (LPL KD)) show improved glucose tolerance and reduced hepatic lipid accumulation with aging compared to wilt type (WT) controls (LPL^flox). To determine the effect of LPL deficiency on neuronal physiology, liver-related neurons were identified in the paraventricular nucleus (PVN) of the hypothalamus using the transsynaptic retrograde tracer PRV-152. Patch-clamp studies revealed reduced inhibitory post-synaptic currents in liver-related neurons of LPL KD mice. Fluorescence lifetime imaging microscopy (FLIM) was used to visualize metabolic changes in LPL-depleted neurons. Quantification of free vs. bound nicotinamide adenine dinucleotide (NADH) and flavin adenine dinucleotide (FAD) revealed increased glucose utilization and TCA cycle flux in LPL-depleted neurons compared to controls. Global metabolomics from hypothalamic cell lines either deficient in or over-expressing LPL recapitulated these findings. Our data suggest that LPL is a novel feature of liver-related preautonomic neurons in the PVN. Moreover, LPL loss is sufficient to cause changes in neuronal substrate utilization and function, which may precede changes in hepatic metabolism. Full article

(This article belongs to the Special Issue Lipid and Lipoprotein Metabolism)

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Review

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14 pages, 1824 KiB

Open AccessReview

Hepatitis C Virus Uses Host Lipids to Its Own Advantage

by Malgorzata Sidorkiewicz

Metabolites 2021, 11(5), 273; https://0-doi-org.brum.beds.ac.uk/10.3390/metabo11050273 - 27 Apr 2021

Cited by 24 | Viewed by 2886

Abstract

Lipids and lipoproteins constitute indispensable components for living not only for humans. In the case of hepatitis C virus (HCV), the option of using the products of our lipid metabolism is “to be, or not to be”. On the other hand, HCV infection, [...] Read more.

Lipids and lipoproteins constitute indispensable components for living not only for humans. In the case of hepatitis C virus (HCV), the option of using the products of our lipid metabolism is “to be, or not to be”. On the other hand, HCV infection, which is the main cause of chronic hepatitis, cirrhosis and hepatocellular carcinoma, exerts a profound influence on lipid and lipoprotein metabolism of the host. The consequences of this alternation are frequently observed as hypolipidemia and hepatic steatosis in chronic hepatitis C (CHC) patients. The clinical relevance of these changes reflects the fact that lipids and lipoprotein play a crucial role in all steps of the life cycle of HCV. The virus circulates in the bloodstream as a highly lipidated lipo-viral particle (LVP) that defines HCV hepatotropism. Thus, strict relationships between lipids/lipoproteins and HCV are indispensable for the mechanism of viral entry into hepatocytes, viral replication, viral particles assembly and secretion. The purpose of this review is to summarize the tricks thanks to which HCV utilizes host lipid metabolism to its own advantage. Full article

(This article belongs to the Special Issue Lipid and Lipoprotein Metabolism)

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22 pages, 2092 KiB

Open AccessReview

Bioactive Ether Lipids: Primordial Modulators of Cellular Signaling

by Nikhil Rangholia, Tina M. Leisner and Stephen P. Holly

Metabolites 2021, 11(1), 41; https://0-doi-org.brum.beds.ac.uk/10.3390/metabo11010041 - 08 Jan 2021

Cited by 22 | Viewed by 4305

Abstract

The primacy of lipids as essential components of cellular membranes is conserved across taxonomic domains. In addition to this crucial role as a semi-permeable barrier, lipids are also increasingly recognized as important signaling molecules with diverse functional mechanisms ranging from cell surface receptor [...] Read more.

The primacy of lipids as essential components of cellular membranes is conserved across taxonomic domains. In addition to this crucial role as a semi-permeable barrier, lipids are also increasingly recognized as important signaling molecules with diverse functional mechanisms ranging from cell surface receptor binding to the intracellular regulation of enzymatic cascades. In this review, we focus on ether lipids, an ancient family of lipids having ether-linked structures that chemically differ from their more prevalent acyl relatives. In particular, we examine ether lipid biosynthesis in the peroxisome of mammalian cells, the roles of selected glycerolipids and glycerophospholipids in signal transduction in both prokaryotes and eukaryotes, and finally, the potential therapeutic contributions of synthetic ether lipids to the treatment of cancer. Full article

(This article belongs to the Special Issue Lipid and Lipoprotein Metabolism)

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14 pages, 1521 KiB

Open AccessReview

Cholesterol Metabolites 25-Hydroxycholesterol and 25-Hydroxycholesterol 3-Sulfate Are Potent Paired Regulators: From Discovery to Clinical Usage

by Yaping Wang, Xiaobo Li and Shunlin Ren

Metabolites 2021, 11(1), 9; https://0-doi-org.brum.beds.ac.uk/10.3390/metabo11010009 - 25 Dec 2020

Cited by 18 | Viewed by 3728

Abstract

Oxysterols have long been believed to be ligands of nuclear receptors such as liver × receptor (LXR), and they play an important role in lipid homeostasis and in the immune system, where they are involved in both transcriptional and posttranscriptional mechanisms. However, they [...] Read more.

Oxysterols have long been believed to be ligands of nuclear receptors such as liver × receptor (LXR), and they play an important role in lipid homeostasis and in the immune system, where they are involved in both transcriptional and posttranscriptional mechanisms. However, they are increasingly associated with a wide variety of other, sometimes surprising, cell functions. Oxysterols have also been implicated in several diseases such as metabolic syndrome. Oxysterols can be sulfated, and the sulfated oxysterols act in different directions: they decrease lipid biosynthesis, suppress inflammatory responses, and promote cell survival. Our recent reports have shown that oxysterol and oxysterol sulfates are paired epigenetic regulators, agonists, and antagonists of DNA methyltransferases, indicating that their function of global regulation is through epigenetic modification. In this review, we explore our latest research of 25-hydroxycholesterol and 25-hydroxycholesterol 3-sulfate in a novel regulatory mechanism and evaluate the current evidence for these roles. Full article

(This article belongs to the Special Issue Lipid and Lipoprotein Metabolism)

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