Publications by authors named "Thorsten Hornemann"

86 Publications

Altered CSF Albumin Quotient Links Peripheral Inflammation and Brain Damage in MS.

Neurol Neuroimmunol Neuroinflamm 2021 03 1;8(2). Epub 2021 Mar 1.

From Neuroimmunology and MS Research (nims) (M.P., P.T.-O., A.L., I.J., M.Z., C.C., W.F., R.M., M.S.), Department of Neurology, University Hospital and University Zurich, Switzerland; Department of Neuroscience DNS (M.P.), University Hospital of Padova, Italy; and Institute for Clinical Chemistry (T.H., A.H.), University Hospital and University Zurich, Switzerland.

Objective: CNS damage can increase the susceptibility of the blood-brain barrier (BBB) to changes induced by systemic inflammation. The aim of this study is to better understand BBB permeability in patients with MS and to examine whether compromised BBB integrity in some of these patients is associated with CNS damage and systemic inflammation.

Methods: Routine CSF measurements of 121 patients with MS were analyzed including number and type of infiltrating cells, total protein, lactate, and oligoclonal bands, as well as intrathecal production of immunoglobulins and CSF/serum quotients for albumin, immunoglobulins, and glucose. In addition, in a subcohort of these patients, we performed ex vivo immunophenotyping of CSF-infiltrating and paired circulating lymphocytes using a panel of 13 monoclonal antibodies, we quantified intrathecal neurofilament light chain (NF-L) and chitinase 3-like 1 (CHI3L1), and we performed intrathecal lipidomic analysis.

Results: Patients with MS with abnormal high levels of albumin in the CSF showed a distinct CSF cell infiltrate and markers of CNS damage such as increased intrathecal levels of NF-L and CHI3L1 as well as a distinct CSF lipidomic profile. In addition, these patients showed higher numbers of circulating proinflammatory Th1 and Th1* cells compatible with systemic inflammation. Of interest, the abnormally high levels of albumin in the CSF of those patients were preserved over time.

Conclusions: Our results support the hypothesis that CNS damage may increase BBB vulnerability to systemic inflammation in a subset of patients and thus contribute to disease heterogeneity.
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http://dx.doi.org/10.1212/NXI.0000000000000951DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7963437PMC
March 2021

Oxidative stress increases 1-deoxysphingolipid levels in chronic kidney disease.

Free Radic Biol Med 2021 Feb 12;164:139-148. Epub 2021 Jan 12.

Key Laboratory of Traditional Chinese Medicine Classical Theory, Ministry of Education, Shandong University of Traditional Chinese Medicine, Jinan, 250355, PR China; Innovation Research Institute of Traditional Chinese Medicine, Shandong University of Traditional Chinese Medicine, Jinan, 250355, PR China; Department of Clinical Pharmacology and Toxicology, University Hospital Zurich, University of Zurich, Zurich, Switzerland. Electronic address:

Chronic kidney disease (CKD) leads to deep changes in lipid metabolism and obvious dyslipidemia. The dysregulation of lipid metabolism in turn results in CKD progression and the complications of cardiovascular diseases. To obtain a profound insight into the associated dyslipidemia in CKD, we performed lipidomic analysis to measure lipid metabolites in the serum from a rat 5/6 nephrectomy (5/6 Nx) model of CKD as well as in the serum from CKD patients. HK-2 cells were also used to examine oxidative stress-induced sphingolipid changes. Totally 182 lipid species were identified in 5/6 Nx rats. We found glycerolipids, total free fatty acids, and sphingolipids levels were significantly upregulated in 5/6 Nx rats. The atypical sphingolipids, 1-deoxysphingolipids, were significantly altered in both CKD animals and human CKD patients. The levels of 1-deoxysphingolipids directly relevant to the level of oxidative stress in vivo and in vitro. These results demonstrate that 1-deoxysphingolipid levels are increased in CKD and this increase directly correlates with increased kidney oxidative stress.
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http://dx.doi.org/10.1016/j.freeradbiomed.2021.01.011DOI Listing
February 2021

Simple Targeted Assays for Metabolic Pathways and Signaling: A Powerful Tool for Targeted Proteomics.

Anal Chem 2020 10 21;92(20):13672-13676. Epub 2020 Sep 21.

Leibniz-Institut für Analytische Wissenschaften - ISAS - e.V., Otto-Hahn-Strasse 6b, 44227 Dortmund, Germany.

We introduce STAMPS, a pathway-centric web service for the development of targeted proteomics assays. STAMPS guides the user by providing several intuitive interfaces for a rapid and simplified method design. Applying our curated framework to signaling and metabolic pathways, we reduced the average assay development time by a factor of ∼150 and revealed that the insulin signaling is actively controlled by protein abundance changes in insulin-sensitive and -resistance states. Although at the current state STAMPS primarily contains mouse data, it was designed for easy extension with additional organisms.
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http://dx.doi.org/10.1021/acs.analchem.0c02793DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7586293PMC
October 2020

Changes in the cerebrospinal fluid lipid profile following subarachnoid hemorrhage in a closed cranium model: Correlations to cerebral vasospasm, neuronal cell death and Interleukin-6 synthesis. A pilot study.

J Stroke Cerebrovasc Dis 2020 Sep 23;29(9):105054. Epub 2020 Jun 23.

Department of Neurosurgery, Kantonsspital Aarau, Aarau, Switzerland; Cerebrovascular Research Group, Department of BioMedical Research, University of Bern, Switzerland. Electronic address:

Background: Phospholipids and sphingolipids are cell membrane components, that participate in signaling events and regulate a wide variety of vital cellular processes. Sphingolipids are involved in ischemic stroke pathophysiology. Throughout cleavage of membrane sphingomyelin by sphingomyelinase in stroke patients, it results in increased Ceramide (Cer) levels in brain tissue. Different studies showed the evidence that sphingomyelinase with Cer production induces expression of interleukin (IL)-6 and have vasoconstrictive proprieties. With this study, we intend to evaluate cerebrospinal fluid (CSF) lipid profile changes in a rabbit closed cranium subarachnoid hemorrhage (SAH) model.

Methods: A total of 14 New Zealand white rabbits were randomly allocated either to SAH or sham group. In the first group SAH was induced by extracranial-intracranial shunting from the subclavian artery into the cisterna magna. Intracranial pressure (ICP) and arterial blood pressure were continuously monitored. Digital subtraction angiography of the basilar artery, CSF and blood samples were performed at day 0 pre SAH and on day 3 post SAH. The amount of IL-6 and various lipids in CSF were quantified using ELISA and Liquid Chromatography-Mass Spectrometry respectively. Cell death was detected in bilateral basal cortex, hippocampus (CA1 and CA3) using terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL).

Results: SAH Induction led to acute increase of ICP and increased delayed cerebral vasospasm (DCVS). At follow up CSF IL-6 levels showed a significant increase compared to baseline. Between baseline and follow up there were no significant differences in any of the measured CSF Lipids irrespective of subgroups. No relevant correlation was found between IL-6 and any of the sphingolipids. We found a correlation between baseline and follow up for the phospholipids phosphatidylethanolamine and phosphatidylcholine.

Conclusions: Neuronal apoptosis, DCVS and IL-6 seems not to be related to changes in CSF lipid profiles except for PEA and PC in a rabbit closed cranium SAH model.
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http://dx.doi.org/10.1016/j.jstrokecerebrovasdis.2020.105054DOI Listing
September 2020

A global lipid map defines a network essential for Zika virus replication.

Nat Commun 2020 07 21;11(1):3652. Epub 2020 Jul 21.

Department of Molecular Microbiology & Immunology, Oregon Health & Science University (OHSU), Portland, OR, 97239, USA.

Zika virus (ZIKV), an arbovirus of global concern, remodels intracellular membranes to form replication sites. How ZIKV dysregulates lipid networks to allow this, and consequences for disease, is poorly understood. Here, we perform comprehensive lipidomics to create a lipid network map during ZIKV infection. We find that ZIKV significantly alters host lipid composition, with the most striking changes seen within subclasses of sphingolipids. Ectopic expression of ZIKV NS4B protein results in similar changes, demonstrating a role for NS4B in modulating sphingolipid pathways. Disruption of sphingolipid biosynthesis in various cell types, including human neural progenitor cells, blocks ZIKV infection. Additionally, the sphingolipid ceramide redistributes to ZIKV replication sites, and increasing ceramide levels by multiple pathways sensitizes cells to ZIKV infection. Thus, we identify a sphingolipid metabolic network with a critical role in ZIKV replication and show that ceramide flux is a key mediator of ZIKV infection.
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http://dx.doi.org/10.1038/s41467-020-17433-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7374707PMC
July 2020

Defects in High Density Lipoprotein metabolism and hepatic steatosis in mice with liver-specific ablation of Hepatocyte Nuclear Factor 4A.

Metabolism 2020 09 3;110:154307. Epub 2020 Jul 3.

Laboratory of Biochemistry, University of Crete Medical School, Heraklion 71003, Greece; Gene Regulation and Genomics group, Institute of Molecular Biology and Biotechnology, Foundation for Research and Technology of Hellas, Heraklion 70013, Greece. Electronic address:

Background: Aberrant concentration, structure and functionality of High Density Lipoprotein (HDL) are associated with many prevalent diseases, including cardiovascular disease and non-alcoholic fatty liver disease (NAFLD). Mice with liver-specific ablation of Hnf4α (H4LivKO) present steatosis and dyslipidemia by mechanisms that are not completely understood. The aim of this study was to explore the role of liver HNF4A in HDL metabolism and the development of steatosis.

Methods And Results: Serum and tissue samples were obtained from 6-weeks old H4LivKO mice and their littermate controls. Liver and serum lipids were measured and HDL structure and functionality were assessed. Global gene expression changes in the liver were analyzed by expression arrays, validations were performed by RT-qPCR and DNA-protein interactions were studied by chromatin immunoprecipitation (ChIP). H4LivKO mice presented liver steatosis, increased liver triglyceride content and decreased concentration of serum total cholesterol, HDL cholesterol, triglycerides, phospholipids and cholesteryl esters. Most classes of phospholipids showed significant changes in species ratio and sphingosine-1-phosphate (S1P) levels were reduced. H4LivKO serum was enriched in the smaller, denser HDL particles, devoid of APOA2 and APOM apolipoproteins, exhibiting decreased activity of paraoxonase-1 but retaining macrophage cholesterol efflux capacity and phospho-AKT activation in endothelial cells. Global gene expression analysis revealed the association of liver HNF4A with known and novel regulators of HDL metabolism as well as NAFLD-susceptibility genes.

Conclusions: HNF4A ablation in mouse liver causes hepatic steatosis, perturbations in HDL structure and function and significant global changes in gene expression. This study reveals new targets of HNF4A involved in HDL metabolism and the development of steatosis and enriches our knowledge on HDL functionality in NAFLD.
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http://dx.doi.org/10.1016/j.metabol.2020.154307DOI Listing
September 2020

Subunit composition of the mammalian serine-palmitoyltransferase defines the spectrum of straight and methyl-branched long-chain bases.

Proc Natl Acad Sci U S A 2020 07 23;117(27):15591-15598. Epub 2020 Jun 23.

Institute of Clinical Chemistry, University Hospital Zurich, University of Zurich, Zurich-8091, Switzerland;

Sphingolipids (SLs) are chemically diverse lipids that have important structural and signaling functions within mammalian cells. SLs are commonly defined by the presence of a long-chain base (LCB) that is normally formed by the conjugation of l-serine and palmitoyl-CoA. This pyridoxal 5-phosphate (PLP)-dependent reaction is mediated by the enzyme serine-palmitoyltransferase (SPT). However, SPT can also metabolize other acyl-CoAs, in the range of C to C, forming a variety of LCBs that differ by structure and function. Mammalian SPT consists of three core subunits: SPTLC1, SPTLC2, and SPTLC3. Whereas SPTLC1 and SPTLC2 are ubiquitously expressed, SPTLC3 expression is restricted to certain tissues only. The influence of the individual subunits on enzyme activity is not clear. Using cell models deficient in SPTLC1, SPTLC2, and SPTLC3, we investigated the role of each subunit on enzyme activity and the LCB product spectrum. We showed that SPTLC1 is essential for activity, whereas SPTLC2 and SPTLC3 are partly redundant but differ in their enzymatic properties. SPTLC1 in combination with SPTLC2 specifically formed C18, C19, and C20 LCBs while the combination of SPTLC1 and SPTLC3 yielded a broader product spectrum. We identified -branched-C18 SO (meC18SO) as the primary product of the SPTLC3 reaction. The meC18SO was synthesized from -methyl-palmitate, in turn synthesized from a precursor metabolite generated in the isoleucine catabolic pathway. The meC18SO is metabolized to ceramides and complex SLs and is a constituent of human low- and high-density lipoproteins.
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http://dx.doi.org/10.1073/pnas.2002391117DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7355037PMC
July 2020

Common and Differential Traits of the Membrane Lipidome of Colon Cancer Cell Lines and their Secreted Vesicles: Impact on Studies Using Cell Lines.

Cancers (Basel) 2020 May 20;12(5). Epub 2020 May 20.

Lipids in Human Pathology, Health Research Institute of the Balearic Islands (IdISBa), Research Unit, University Hospital Son Espases, 07120 Palma, Spain.

Colorectal cancer (CRC) is the fourth leading cause of cancer death in the world. Despite the screening programs, its incidence in the population below the 50s is increasing. Therefore, new stratification protocols based on multiparametric approaches are highly needed. In this scenario, the lipidome is emerging as a powerful tool to classify tumors, including CRC, wherein it has proven to be highly sensitive to cell malignization. Hence, the possibility to describe the lipidome at the level of lipid species has renewed the interest to investigate the role of specific lipid species in pathologic mechanisms, being commercial cell lines, a model still heavily used for this purpose. Herein, we characterize the membrane lipidome of five commercial colon cell lines and their extracellular vesicles (EVs). The results demonstrate that both cell and EVs lipidome was able to segregate cells according to their malignancy. Furthermore, all CRC lines shared a specific and strikingly homogenous impact on ether lipid species. Finally, this study also cautions about the need of being aware of the singularities of each cell line at the level of lipid species. Altogether, this study firmly lays the groundwork of using the lipidome as a solid source of tumor biomarkers.
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http://dx.doi.org/10.3390/cancers12051293DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7281030PMC
May 2020

Serine administration as a novel prophylactic approach to reduce the severity of acute pancreatitis during diabetes in mice.

Diabetologia 2020 09 8;63(9):1885-1899. Epub 2020 May 8.

Swiss Hepato-Pancreato-Biliary Center, Department of Visceral and Transplantation Surgery, University Hospital Zurich, Zurich, Switzerland.

Aims/hypothesis: Compared with the general population, individuals with diabetes have a higher risk of developing severe acute pancreatitis, a highly debilitating and potentially lethal inflammation of the exocrine pancreas. In this study, we investigated whether 1-deoxysphingolipids, atypical lipids that increase in the circulation following the development of diabetes, exacerbate the severity of pancreatitis in a diabetic setting.

Methods: We analysed whether administration of an L-serine-enriched diet to mouse models of diabetes, an established method for decreasing the synthesis of 1-deoxysphingolipids in vivo, reduced the severity of acute pancreatitis. Furthermore, we elucidated the molecular mechanisms underlying the lipotoxicity exerted by 1-deoxysphingolipids towards rodent pancreatic acinar cells in vitro.

Results: We demonstrated that L-serine supplementation reduced the damage of acinar tissue resulting from the induction of pancreatitis in diabetic mice (average histological damage score: 1.5 in L-serine-treated mice vs 2.7 in the control group). At the cellular level, we showed that L-serine decreased the production of reactive oxygen species, endoplasmic reticulum stress and cellular apoptosis in acinar tissue. Importantly, these parameters, together with DNA damage, were triggered in acinar cells upon treatment with 1-deoxysphingolipids in vitro, suggesting that these lipids are cytotoxic towards pancreatic acinar cells in a cell-autonomous manner. In search of the initiating events of the observed cytotoxicity, we discovered that 1-deoxysphingolipids induced early mitochondrial dysfunction in acinar cells, characterised by ultrastructural alterations, impaired oxygen consumption rate and reduced ATP synthesis.

Conclusions/interpretation: Our results suggest that 1-deoxysphingolipids directly damage the functionality of pancreatic acinar cells and highlight that an L-serine-enriched diet may be used as a promising prophylactic intervention to reduce the severity of pancreatitis in the context of diabetes.
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http://dx.doi.org/10.1007/s00125-020-05156-xDOI Listing
September 2020

Intrahepatic Fat and Postprandial Glycemia Increase After Consumption of a Diet Enriched in Saturated Fat Compared With Free Sugars.

Diabetes Care 2020 05 12;43(5):1134-1141. Epub 2020 Mar 12.

Oxford Centre for Diabetes, Endocrinology and Metabolism, University of Oxford, Churchill Hospital, Oxford, U.K.

Objective: Debate continues regarding the influence of dietary fats and sugars on the risk of developing metabolic diseases, including insulin resistance and nonalcoholic fatty liver disease (NAFLD). We investigated the effect of two eucaloric diets, one enriched with saturated fat (SFA) and the other enriched with free sugars (SUGAR), on intrahepatic triacylglycerol (IHTAG) content, hepatic de novo lipogenesis (DNL), and whole-body postprandial metabolism in overweight males.

Research Design And Methods: Sixteen overweight males were randomized to consume the SFA or SUGAR diet for 4 weeks before consuming the alternate diet after a 7-week washout period. The metabolic effects of the respective diets on IHTAG content, hepatic DNL, and whole-body metabolism were investigated using imaging techniques and metabolic substrates labeled with stable-isotope tracers.

Results: Consumption of the SFA diet significantly increased IHTAG by mean ± SEM 39.0 ± 10.0%, while after the SUGAR diet IHTAG was virtually unchanged. Consumption of the SFA diet induced an exaggerated postprandial glucose and insulin response to a standardized test meal compared with SUGAR. Although whole-body fat oxidation, lipolysis, and DNL were similar following the two diets, consumption of the SUGAR diet resulted in significant ( < 0.05) decreases in plasma total, HDL, and non-HDL cholesterol and fasting β-hydroxybutyrate plasma concentrations.

Conclusions: Consumption of an SFA diet had a potent effect, increasing IHTAG together with exaggerating postprandial glycemia. The SUGAR diet did not influence IHTAG and induced minor metabolic changes. Our findings indicate that a diet enriched in SFA is more harmful to metabolic health than a diet enriched in free sugars.
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http://dx.doi.org/10.2337/dc19-2331DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7171936PMC
May 2020

Farnesoid X receptor activation induces the degradation of hepatotoxic 1-deoxysphingolipids in non-alcoholic fatty liver disease.

Liver Int 2020 04 8;40(4):844-859. Epub 2020 Jan 8.

Department of Clinical Pharmacology and Toxicology, University Hospital Zurich, University of Zurich, Zurich, Switzerland.

Background & Aims: Patients with non-alcoholic fatty liver disease (NAFLD) exhibit higher levels of plasma 1-deoxysphingolipids than healthy individuals. The aim of this study was to investigate the role of farnesoid X receptor (FXR) in 1-deoxysphingolipid de novo synthesis and degradation.

Methods: Mice were fed with a high-fat diet (HFD) to induce obesity and NAFLD, and then treated with the FXR ligand obeticholic acid (OCA). Histology and gene expression analysis were performed on liver tissue. Sphingolipid patterns from NAFLD patients and mouse models were assessed by liquid chromatography-mass spectrometry. The molecular mechanism underlying the effect of FXR activation on sphingolipid metabolism was studied in Huh7 cells and primary cultured hepatocytes, as well as in a 1-deoxysphinganine-treated mouse model.

Results: 1-deoxysphingolipids were increased in both NAFLD patients and mouse models. FXR activation by OCA protected the liver against oxidative stress, apoptosis, and reduced 1-deoxysphingolipid levels, both in a HFD-induced mouse model of obesity and in 1-deoxysphinganine-treated mice. In vitro, FXR activation lowered intracellular 1-deoxysphingolipid levels by inducing Cyp4f-mediated degradation, but not by inhibiting de novo synthesis, thereby protecting hepatocytes against doxSA-induced cytotoxicity, mitochondrial damage, and apoptosis. Overexpression of Cyp4f13 in cells was sufficient to ameliorate doxSA-induced cytotoxicity. Treatment with the Cyp4f pan-inhibitor HET0016 or FXR knock-down fully abolished the protective effect of OCA, indicating that OCA-mediated 1-deoxysphingolipid degradation is FXR and Cyp4f dependent.

Conclusions: Our study identifies FXR-Cyp4f as a novel regulatory pathway for 1-deoxysphingolipid metabolism. FXR activation represents a promising therapeutic strategy for patients with metabolic syndrome and NAFLD.
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http://dx.doi.org/10.1111/liv.14340DOI Listing
April 2020

FADS3 is a Δ14Z sphingoid base desaturase that contributes to gender differences in the human plasma sphingolipidome.

J Biol Chem 2020 02 20;295(7):1889-1897. Epub 2019 Dec 20.

Institute for Clinical Chemistry, University Hospital and University Zurich, 8091 Zürich, Switzerland. Electronic address:

Sphingolipids (SLs) are structurally diverse lipids that are defined by the presence of a long-chain base (LCB) backbone. Typically, LCBs contain a single Δ4E double bond (DB) (mostly d18:1), whereas the dienic LCB sphingadienine (d18:2) contains a second DB at the Δ14Z position. The enzyme introducing the Δ14Z DB is unknown. We analyzed the LCB plasma profile in a gender-, age-, and BMI-matched subgroup of the CoLaus cohort ( = 658). Sphingadienine levels showed a significant association with gender, being on average ∼30% higher in females. A genome-wide association study (GWAS) revealed variants in the fatty acid desaturase 3 () gene to be significantly associated with the plasma d18:2/d18:1 ratio ( = -log 7.9). Metabolic labeling assays, FADS3 overexpression and knockdown approaches, and plasma LCB profiling in FADS3-deficient mice confirmed that FADS3 is a LCB desaturase and required for the introduction of the Δ14Z double bond. Moreover, we showed that FADS3 is required for the conversion of the atypical cytotoxic 1-deoxysphinganine (1-deoxySA, m18:0) to 1-deoxysphingosine (1-deoxySO, m18:1). HEK293 cells overexpressing FADS3 were more resistant to m18:0 toxicity than WT cells. In summary, using a combination of metabolic profiling and GWAS, we identified FADS3 to be essential for forming Δ14Z DB containing LCBs, such as d18:2 and m18:1. Our results unravel FADS3 as a Δ14Z LCB desaturase, thereby disclosing the last missing enzyme of the SL synthesis pathway.
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http://dx.doi.org/10.1074/jbc.AC119.011883DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7029104PMC
February 2020

Structure-function relationships of HDL in diabetes and coronary heart disease.

JCI Insight 2020 01 16;5(1). Epub 2020 Jan 16.

Institute of Clinical Chemistry, University of Zurich and University Hospital of Zurich, Zurich, Switzerland.

High-density lipoproteins (HDL) contain hundreds of lipid species and proteins and exert many potentially vasoprotective and antidiabetogenic activities on cells. To resolve structure-function-disease relationships of HDL, we characterized HDL of 51 healthy subjects and 98 patients with diabetes (T2DM), coronary heart disease (CHD), or both for protein and lipid composition, as well as functionality in 5 cell types. The integration of 40 clinical characteristics, 34 nuclear magnetic resonance (NMR) features, 182 proteins, 227 lipid species, and 12 functional read-outs by high-dimensional statistical modeling revealed, first, that CHD and T2DM are associated with different changes of HDL in size distribution, protein and lipid composition, and function. Second, different cellular functions of HDL are weakly correlated with each other and determined by different structural components. Cholesterol efflux capacity (CEC) was no proxy of other functions. Third, 3 potentially novel determinants of HDL function were identified and validated by the use of artificially reconstituted HDL, namely the sphingadienine-based sphingomyelin SM 42:3 and glycosylphosphatidylinositol-phospholipase D1 for the ability of HDL to inhibit starvation-induced apoptosis of human aortic endothelial cells and apolipoprotein F for the ability of HDL to promote maximal respiration of brown adipocytes.
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http://dx.doi.org/10.1172/jci.insight.131491DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7030825PMC
January 2020

Macrophage NCOR1 protects from atherosclerosis by repressing a pro-atherogenic PPARγ signature.

Eur Heart J 2020 03;41(9):995-1005

Center for Molecular Cardiology, University of Zurich, Wagistrasse 12, 8952 Schlieren, Switzerland.

Aims: Nuclear receptors and their cofactors regulate key pathophysiological processes in atherosclerosis development. The transcriptional activity of these nuclear receptors is controlled by the nuclear receptor corepressors (NCOR), scaffolding proteins that form the basis of large corepressor complexes. Studies with primary macrophages demonstrated that the deletion of Ncor1 increases the expression of atherosclerotic molecules. However, the role of nuclear receptor corepressors in atherogenesis is unknown.

Methods And Results: We generated myeloid cell-specific Ncor1 knockout mice and crossbred them with low-density lipoprotein receptor (Ldlr) knockouts to study the role of macrophage NCOR1 in atherosclerosis. We demonstrate that myeloid cell-specific deletion of nuclear receptor corepressor 1 (NCOR1) aggravates atherosclerosis development in mice. Macrophage Ncor1-deficiency leads to increased foam cell formation, enhanced expression of pro-inflammatory cytokines, and atherosclerotic lesions characterized by larger necrotic cores and thinner fibrous caps. The immunometabolic effects of NCOR1 are mediated via suppression of peroxisome proliferator-activated receptor gamma (PPARγ) target genes in mouse and human macrophages, which lead to an enhanced expression of the CD36 scavenger receptor and subsequent increase in oxidized low-density lipoprotein uptake in the absence of NCOR1. Interestingly, in human atherosclerotic plaques, the expression of NCOR1 is reduced whereas the PPARγ signature is increased, and this signature is more pronounced in ruptured compared with non-ruptured carotid plaques.

Conclusions: Our findings show that macrophage NCOR1 blocks the pro-atherogenic functions of PPARγ in atherosclerosis and suggest that stabilizing the NCOR1-PPARγ binding could be a promising strategy to block the pro-atherogenic functions of plaque macrophages and lesion progression in atherosclerotic patients.
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http://dx.doi.org/10.1093/eurheartj/ehz667DOI Listing
March 2020

The ORMDL3 asthma susceptibility gene regulates systemic ceramide levels without altering key asthma features in mice.

J Allergy Clin Immunol 2019 12 20;144(6):1648-1659.e9. Epub 2019 Jul 20.

Laboratory of Mucosal Immunology and Immunoregulation, VIB Center for Inflammation Research, Ghent, Belgium; Department of Internal Medicine and Pediatrics, Ghent University, Ghent, Belgium; Department of Pulmonary Medicine, Erasmus Medical Center, Rotterdam, The Netherlands. Electronic address:

Background: Genome-wide association studies in asthma have repeatedly identified single nucleotide polymorphisms in the ORM (yeast)-like protein isoform 3 (ORMDL3) gene across different populations. Although the ORM homologues in yeast are well-known inhibitors of sphingolipid synthesis, it is still unclear whether and how mammalian ORMDL3 regulates sphingolipid metabolism and whether altered sphingolipid synthesis would be causally related to asthma risk.

Objective: We sought to examine the in vivo role of ORMDL3 in sphingolipid metabolism and allergic asthma.

Methods: Ormdl3-LacZ reporter mice, gene-deficient Ormdl3 mice, and overexpressing Ormdl3 mice were exposed to physiologically relevant aeroallergens, such as house dust mite (HDM) or Alternaria alternata, to induce experimental asthma. Mass spectrometry-based sphingolipidomics were performed, and airway eosinophilia, T2 cytokine production, immunoglobulin synthesis, airway remodeling, and bronchial hyperreactivity were measured.

Results: HDM challenge significantly increased levels of total sphingolipids in the lungs of HDM-sensitized mice compared with those in control mice. In Ormdl3 mice the allergen-induced increase in lung ceramide levels was significantly reduced, whereas total sphingolipid levels were not affected. Conversely, in liver and serum, levels of total sphingolipids, including ceramides, were increased in Ormdl3 mice, whereas they were decreased in Ormdl3 mice. This difference was independent of allergen exposure. Despite these changes, all features of asthma were identical between wild-type, Ormdl3, and Ormdl3 mice across several models of experimental asthma.

Conclusion: ORMDL3 regulates systemic ceramide levels, but genetically interfering with Ormdl3 expression does not result in altered experimental asthma.
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http://dx.doi.org/10.1016/j.jaci.2019.06.041DOI Listing
December 2019

Body weight-dependent and independent improvement in lipid metabolism after Roux-en-Y gastric bypass in ApoE*3Leiden.CETP mice.

Int J Obes (Lond) 2019 12 3;43(12):2394-2406. Epub 2019 Jul 3.

Institute of Veterinary Physiology, Vetsuisse Faculty University of Zurich, Zurich, Switzerland.

Background/objectives: The incidence of obesity and metabolic syndrome (MetS) has rapidly increased worldwide. Roux-en-Y gastric bypass (RYGB) achieves long-term weight loss and improves MetS-associated comorbidities. Using a mouse model with a humanized lipoprotein metabolism, we elucidated whether improvements in lipid and glucose metabolism after RYGB surgery are body weight loss-dependent or not.

Subjects/methods: Male ApoE*3Leiden.CETP (ApoE3L.CETP) mice fed Western type diet for 6 weeks underwent RYGB or Sham surgery. Sham groups were either fed ad libitum or were body weight-matched (BWm) to the RYGB mice to discriminate surgical effects from body weight loss-associated effects. Before and after surgery, plasma was collected to assess the metabolic profile, and glucose tolerance and insulin sensitivity were tested. Twenty days after surgery, mice were sacrificed, and liver was collected to assess metabolic, histological and global gene expression changes after surgery.

Results: RYGB induced a marked reduction in body weight, which was also achieved by severe food restriction in BWm mice, and total fat mass compared to Sham ad libitum mice (Sham AL). Total cholesterol, non-high-density lipoprotein cholesterol (non-HDL-C) and ceramide were strongly reduced 20 days after surgery in RYGB compared to BWm mice. Glucose tolerance and insulin sensitivity improved 13 days after surgery similarly in RYGB and BWm mice. Liver histology confirmed lipid reduction in RYGB and BWm mice while the transcriptomics data indicated altered genes expression in lipid metabolism.

Conclusions: RYGB surgery improves glucose metabolism and greatly ameliorates lipid metabolism in part in a body weight-dependent manner. Given that ApoE3L.CETP mice were extensively studied to describe the MetS, and given that RYGB improved ceramide after surgery, our data confirmed the usefulness of ApoE3L.CETP mice after RYGB in deciphering the metabolic improvements to treat the MetS.
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http://dx.doi.org/10.1038/s41366-019-0408-yDOI Listing
December 2019

Development of MRC Centre MRI calf muscle fat fraction protocol as a sensitive outcome measure in Hereditary Sensory Neuropathy Type 1.

J Neurol Neurosurg Psychiatry 2019 08 17;90(8):895-906. Epub 2019 Apr 17.

MRC Centre for Neuromuscular Diseases, UCL Institute of Neurology and National Hospital for Neurology and Neurosurgery, London, UK

Objectives: Hereditary sensory neuropathy type 1 (HSN1) is a rare, slowly progressive neuropathy causing profound sensory deficits and often severe motor loss. L-serine supplementation is a possible candidate therapy but the lack of responsive outcome measures is a barrier for undertaking clinical trials in HSN1. We performed a 12-month natural history study to characterise the phenotype of HSN1 and to identify responsive outcome measures.

Methods: Assessments included Charcot-Marie-Tooth Neuropathy Score version 2 (CMTNSv2), CMTNSv2-Rasch modified, nerve conduction studies, quantitative sensory testing, intraepidermal nerve fibre density (thigh), computerised myometry (lower limbs), plasma 1-deoxysphingolipid levels, calf-level intramuscular fat accumulation by MRI and patient-based questionnaires (Neuropathic Pain Symptom Inventory and 36-Short Form Health Survey version 2 [SF-36v2]).

Results: 35 patients with HSN1 were recruited. There was marked heterogeneity in the phenotype mainly due to differences between the sexes: males generally more severely affected. The outcome measures that significantly changed over 1 year and correlated with CMTNSv2, SF-36v2-physical component and disease duration were MRI determined calf intramuscular fat accumulation (mean change in overall calf fat fraction 2.36%, 95% CI 1.16 to 3.55, p=0.0004), pressure pain threshold on the hand (mean change 40 kPa, 95% CI 0.7 to 80, p=0.046) and myometric measurements of ankle plantar flexion (median change -0.5 Nm, IQR -9.5 to 0, p=0.0007), ankle inversion (mean change -0.89 Nm, 95% CI -1.66 to -0.12, p=0.03) and eversion (mean change -1.61 Nm, 95% CI -2.72 to -0.51, p=0.006). Intramuscular calf fat fraction was the most responsive outcome measure.

Conclusion: MRI determined calf muscle fat fraction shows validity and high responsiveness over 12 months and will be useful in HSN1 clinical trials.
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http://dx.doi.org/10.1136/jnnp-2018-320198DOI Listing
August 2019

A Novel Variant (Asn177Asp) in SPTLC2 Causing Hereditary Sensory Autonomic Neuropathy Type 1C.

Neuromolecular Med 2019 06 6;21(2):182-191. Epub 2019 Apr 6.

Institute for Clinical Chemistry, University Hospital Zurich, University of Zurich, Wagistrasse 14 Schlieren, 8952, Zurich, Switzerland.

Hereditary sensory and autonomic neuropathy type 1 (HSAN1) is a rare, autosomal dominantly inherited, slowly progressive and length-dependent axonal peripheral neuropathy. HSAN1 is associated with several mutations in serine-palmitoyltransferase (SPT), the first enzyme in the de novo sphingolipid biosynthetic pathway. HSAN1 mutations alter the substrate specificity of SPT, which leads to the formation of 1-deoxysphingolipids, an atypical and neurotoxic subclass of sphingolipids. This study describes the clinical and neurophysiological phenotype of a German family with a novel SPTCL2 mutation (c.529A > G; N177D) associated with HSAN1 and the biochemical characterization of this mutation.) The mutaion was identified in five family members that segregated with the diesease. Patients were characterized genetically and clinically for neurophysiological function. Their plasma sphingolipid profiles were analyzed by LC-MS. The biochemical properties of the mutation were characterized in a cell-based activity assay. Affected family members showed elevated 1-deoxysphingolipid plasma levels. HEK293 cells expressing the N177D SPTLC2 mutant showed increased de novo 1-deoxysphingolipid formation, but also displayed elevated canonical SPT activity and increased C20 sphingoid base production. This study identifies the SPTLC2 N177D variant as a novel disease-causing mutation with increased 1-deoxySL formation and its association with a typical HSAN1 phenotype.
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http://dx.doi.org/10.1007/s12017-019-08534-wDOI Listing
June 2019

Hereditary sensory and autonomic neuropathy type IC accompanied by upper motor neuron abnormalities and type II juxtafoveal retinal telangiectasias.

J Peripher Nerv Syst 2019 06 4;24(2):224-229. Epub 2019 Apr 4.

Department of Neurology, Concord Repatriation General Hospital, Sydney, New South Wales, Australia.

Hereditary sensory and autonomic neuropathy type I (HSAN-1) is an autosomal dominant sensory neuropathy occurring secondary to mutations in the SPTLC1 and SPTLC2 genes. We present two generations of a single family with Ser384Phe mutation in the SPTLC2 gene located on chromosome 14q24 characterized by a typical HSAN-1c presentation, with additional findings upper motor neuron signs, early demyelinating features on nerve conduction studies, and type II juxtafoveal retinal telangiectasias also known as macular telangiectasias (MacTel II). Although HSAN1 is characterized as an axonal neuropathy, demyelinating features were identified in two subjects on serial nerve conduction studies comprising motor conduction block, temporal dispersion, and prolongation of F-waves. MacTell II is a rare syndrome characterized by bilateral macular depigmentation and Müller cell loss. It has a presumed genetic basis, and these cases suggest that the accumulation of toxic sphingoplipids may lead to Müller cell degeneration, subsequent neuronal loss, depigmentation, and progressive central macular thinning.
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http://dx.doi.org/10.1111/jns.12315DOI Listing
June 2019

Impaired ABCA1/ABCG1-mediated lipid efflux in the mouse retinal pigment epithelium (RPE) leads to retinal degeneration.

Elife 2019 03 13;8. Epub 2019 Mar 13.

Lab for Retinal Cell Biology, Department of Ophthalmology, University of Zurich, Schlieren, Switzerland.

Age-related macular degeneration (AMD) is a progressive disease of the retinal pigment epithelium (RPE) and the retina leading to loss of central vision. Polymorphisms in genes involved in lipid metabolism, including the ATP-binding cassette transporter A1 (), have been associated with AMD risk. However, the significance of retinal lipid handling for AMD pathogenesis remains elusive. Here, we study the contribution of lipid efflux in the RPE by generating a mouse model lacking ABCA1 and its partner ABCG1 specifically in this layer. Mutant mice show lipid accumulation in the RPE, reduced RPE and retinal function, retinal inflammation and RPE/photoreceptor degeneration. Data from human cell lines indicate that the AMD risk-conferring allele decreases expression, identifying the potential molecular cause that underlies the genetic risk for AMD. Our results highlight the essential homeostatic role for lipid efflux in the RPE and suggest a pathogenic contribution of reduced ABCA1 function to AMD.
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http://dx.doi.org/10.7554/eLife.45100DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6435327PMC
March 2019

Obesity-induced activation of JunD promotes myocardial lipid accumulation and metabolic cardiomyopathy.

Eur Heart J 2019 03;40(12):997-1008

Center for Molecular Cardiology, University of Zürich, Wagistrasse 12, Schlieren, Switzerland.

Aims: Metabolic cardiomyopathy (MC)-characterized by intra-myocardial triglyceride (TG) accumulation and lipotoxic damage-is an emerging cause of heart failure in obese patients. Yet, its mechanisms remain poorly understood. The Activator Protein 1 (AP-1) member JunD was recently identified as a key modulator of hepatic lipid metabolism in obese mice. The present study investigates the role of JunD in obesity-induced MC.

Methods And Results: JunD transcriptional activity was increased in hearts from diet-induced obese (DIO) mice and was associated with myocardial TG accumulation and left ventricular (LV) dysfunction. Obese mice lacking JunD were protected against MC. In DIO hearts, JunD directly binds PPARγ promoter thus enabling transcription of genes involved in TG synthesis, uptake, hydrolysis, and storage (i.e. Fas, Cd36, Lpl, Plin5). Cardiac-specific overexpression of JunD in lean mice led to PPARγ activation, cardiac steatosis, and dysfunction, thereby mimicking the MC phenotype. In DIO hearts as well as in neonatal rat ventricular myocytes exposed to palmitic acid, Ago2 immunoprecipitation, and luciferase assays revealed JunD as a direct target of miR-494-3p. Indeed, miR-494-3p was down-regulated in hearts from obese mice, while its overexpression prevented lipotoxic damage by suppressing JunD/PPARγ signalling. JunD and miR-494-3p were also dysregulated in myocardial specimens from obese patients as compared with non-obese controls, and correlated with myocardial TG content, expression of PPARγ-dependent genes, and echocardiographic indices of LV dysfunction.

Conclusion: miR-494-3p/JunD is a novel molecular axis involved in obesity-related MC. These results pave the way for approaches to prevent or treat LV dysfunction in obese patients.
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http://dx.doi.org/10.1093/eurheartj/ehy903DOI Listing
March 2019

Randomized trial of l-serine in patients with hereditary sensory and autonomic neuropathy type 1.

Neurology 2019 01 9;92(4):e359-e370. Epub 2019 Jan 9.

From the Department of Neurology (V.F., W.D., K.W., R.A.-B., A.L.O., F.E.), Biostatistics Center, Department of Medicine (E.A.M.), and Department of Pathology (Neuropathology) (A.L.O.), Massachusetts General Hospital, Harvard Medical School, Boston; Clinical Chemistry (S.S., T.H.), University Hospital Zurich, Switzerland; and University of Massachusetts Medical School (P.N., D.M.-Y., R.B.), Worcester.

Objective: To evaluate the safety and efficacy of l-serine in humans with hereditary sensory autonomic neuropathy type I (HSAN1).

Methods: In this randomized, placebo-controlled, parallel-group trial with open-label extension, patients aged 18-70 years with symptomatic HSAN1 were randomized to l-serine (400 mg/kg/day) or placebo for 1 year. All participants received l-serine during the second year. The primary outcome measure was the Charcot-Marie-Tooth Neuropathy Score version 2 (CMTNS). Secondary outcomes included plasma sphingolipid levels, epidermal nerve fiber density, electrophysiologic measurements, patient-reported measures, and adverse events.

Results: Between August 2013 and April 2014, we enrolled and randomized 18 participants, 16 of whom completed the study. After 1 year, the l-serine group experienced improvement in CMTNS relative to the placebo group (-1.5 units, 95% CI -2.8 to -0.1, = 0.03), with evidence of continued improvement in the second year of treatment (-0.77, 95% CI -1.67 to 0.13, = 0.09). Concomitantly, deoxysphinganine levels dropped in l-serine-treated but not placebo-treated participants (59% decrease vs 11% increase; < 0.001). There were no serious adverse effects related to l-serine.

Conclusion: High-dose oral l-serine supplementation appears safe in patients with HSAN1 and is potentially effective at slowing disease progression.

Clinicaltrialsgov Identifier: NCT01733407.

Classification Of Evidence: This study provides Class I evidence that high-dose oral l-serine supplementation significantly slows disease progression in patients with HSAN1.
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http://dx.doi.org/10.1212/WNL.0000000000006811DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6345118PMC
January 2019

DEGS1-associated aberrant sphingolipid metabolism impairs nervous system function in humans.

J Clin Invest 2019 03 11;129(3):1229-1239. Epub 2019 Feb 11.

Institute of Human Genetics, Medical Faculty, RWTH Aachen University, Aachen, Germany.

Background: Sphingolipids are important components of cellular membranes and functionally associated with fundamental processes such as cell differentiation, neuronal signaling, and myelin sheath formation. Defects in the synthesis or degradation of sphingolipids leads to various neurological pathologies; however, the entire spectrum of sphingolipid metabolism disorders remains elusive.

Methods: A combined approach of genomics and lipidomics was applied to identify and characterize a human sphingolipid metabolism disorder.

Results: By whole-exome sequencing in a patient with a multisystem neurological disorder of both the central and peripheral nervous systems, we identified a homozygous p.Ala280Val variant in DEGS1, which catalyzes the last step in the ceramide synthesis pathway. The blood sphingolipid profile in the patient showed a significant increase in dihydro sphingolipid species that was further recapitulated in patient-derived fibroblasts, in CRISPR/Cas9-derived DEGS1-knockout cells, and by pharmacological inhibition of DEGS1. The enzymatic activity in patient fibroblasts was reduced by 80% compared with wild-type cells, which was in line with a reduced expression of mutant DEGS1 protein. Moreover, an atypical and potentially neurotoxic sphingosine isomer was identified in patient plasma and in cells expressing mutant DEGS1.

Conclusion: We report DEGS1 dysfunction as the cause of a sphingolipid disorder with hypomyelination and degeneration of both the central and peripheral nervous systems.

Trial Registration: Not applicable.

Funding: Seventh Framework Program of the European Commission, Swiss National Foundation, Rare Disease Initiative Zurich.
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http://dx.doi.org/10.1172/JCI124159DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6391115PMC
March 2019

The Impact of Roux-en-Y Gastric Bypass on Bone Remodeling Expressed by the P1NP/βCTX Ratio: a Single-Center Prospective Cohort Study.

Obes Surg 2019 04;29(4):1185-1194

Department of Surgery and Transplantation, University Hospital Zurich, CH-8091, Zurich, Switzerland.

Background: Bariatric surgery seems to decrease bone mineral density and increase the risk of fatigue fractures. P1NP (bone formation) and βCTX (bone resorption) were recently validated as reference bone turnover markers (BTM).

Objective: To assess changes in bone remodeling in severely obese patients undergoing Roux-en-Y gastric bypass (RYGB) by using a new composite biomarker, the P1NP/βCTX ratio.

Methods: We prospectively collected blood samples preoperatively, at 1 month and at 1 year from 114 consecutive RYGB patients from 12/2012 to 04/2014. Repeated measures ANOVA and multiple regression were used for data analysis. Cumulative incidence of fractures was assessed in 06/2018.

Results: The P1NP/βCTX ratio decreased significantly (P < 0.001) from baseline to 1 month and 1 year (180 ± 6.6, 110 ± 4.1, and 132 ± 5.4). The 1-year P1NP/βCTX ratio did not correlate with BMI or ΔBMI, but inversely correlated with age (r = - 0.23, P = 0.014) and with hsCRP (r = - 0.26, P = 0.009), even after adjustment for age, sex, BMI, and lifestyle, and linearly correlated with albumin (r = 0.2, P = 0.037). At baseline, none of these correlations were detectable. Serum for all time-points was available from > 94% of the patients. At a median follow-up of 4.7 years, 8 patients (7.3%) had a bone fracture, all of them traumatic.

Conclusion: Following RYGB, bone remodeling increases, with a shift toward degradation. This effect seems to be weight-loss independent and shows a correlation with age, with the level of systemic inflammation, and with nutritional state. The risk of fractures should be assessed systematically in bariatric patients and measures of prevention should be improved accordingly.
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http://dx.doi.org/10.1007/s11695-018-03640-3DOI Listing
April 2019

[CME Laboratory 57/Answers: Preanalytics].

Praxis (Bern 1994) 2018;107(20):1111-1112

1 Institut für Klinische Chemie, IKC OPS E21, Universitätskrankenhaus Zürich.

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http://dx.doi.org/10.1024/1661-8157/a003075DOI Listing
December 2018

[CME Laboratory 57: Preanalytics].

Praxis (Bern 1994) 2018 Sep;107(19):1013-1014

1 Institut für Klinische Chemie, IKC OPS E21, Universitätskrankenhaus Zürich.

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http://dx.doi.org/10.1024/1661-8157/a003074DOI Listing
September 2018

Disturbed sphingolipid metabolism with elevated 1-deoxysphingolipids in glycogen storage disease type I - A link to metabolic control.

Mol Genet Metab 2018 09 20;125(1-2):73-78. Epub 2018 Jul 20.

Division of Endocrinology, Diabetes, and Clinical Nutrition, University Hospital Zurich, Zurich, Switzerland; Radiz - Rare Disease Initiative Zurich, Clinical Research Priority Program for Rare Diseases, University of Zurich, Switzerland. Electronic address:

Background: 1-Deoxysphingolipids (1-deoxySLs) are atypical sphingolipids. They are formed during sphingolipid de novo synthesis by the enzyme serine palmitoyltransferase, due to the alternate use of alanine over its canonical substrate serine. Pathologically elevated 1-deoxySL are involved in several neurological and metabolic disorders. The objective of this study was to investigate the role of 1-deoxySL in glycogen storage disease type I (GSDI).

Methods: In this prospective, longitudinal observational study (median follow-up 1.8y), the plasma 1-deoxySL profile was analyzed in 15 adult GSDI patients (12 GSDIa, 3 GSDIb), and 31 healthy controls, along with standard parameters for monitoring GSDI.

Results: 1-Deoxysphinganine (1-deoxySA) concentrations were elevated in GSDI compared to controls (191 ± 129 vs 35 ± 14 nmol/l, p < 0.0001). Concordant with the mechanism of 1-deoxySL synthesis, plasma alanine was higher (625 ± 182 vs 398 ± 90 μmol/l, p < 0.0001), while serine was lower in GSDI than in controls (88 ± 22 vs 110 ± 18 μmol/l. p < 0.001). Accordingly, serine, alanine and triglycerides were determinants of 1-deoxySA in the longitudinal analysis of GSDIa. 1-deoxySA concentrations correlated with the occurrence of low blood glucose (area under the curve below 4 mmol/l) in continuous glucose monitoring. The 1-deoxySL profile in GSDIb was distinct from GSDIa, with a different ratio of saturated to unsaturated 1-deoxySL.

Conclusion: In addition to the known abnormalities of lipoproteins, GSDI patients also have a disturbed sphingolipid metabolism with elevated plasma 1-deoxySL concentrations. 1-DeoxySA relates to the occurrence of low blood glucose, and may constitute a potential new biomarker for assessing metabolic control. GSDIa and Ib have distinct 1-deoxySL profiles indicating that both GSD subtypes have diverse phenotypes regarding lipid metabolism.
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http://dx.doi.org/10.1016/j.ymgme.2018.07.003DOI Listing
September 2018

Differential-Mobility Spectrometry of 1-Deoxysphingosine Isomers: New Insights into the Gas Phase Structures of Ionized Lipids.

Anal Chem 2018 04 6;90(8):5343-5351. Epub 2018 Apr 6.

Central Analytical Research Facility, Institute for Future Environments , Queensland University of Technology , Brisbane , Queensland 4001 , Australia.

Separation and structural identification of lipids remain a major challenge for contemporary lipidomics. Regioisomeric lipids differing only in position(s) of unsaturation are often not differentiated by conventional liquid chromatography-mass spectrometry approaches leading to the incomplete, or sometimes incorrect, assignation of molecular structure. Here we describe an investigation of the gas phase separations by differential-mobility spectrometry (DMS) of a series of synthetic analogues of the recently described 1-deoxysphingosine. The dependence of the DMS behavior on the position of the carbon-carbon double bond within the ionized lipid is systematically explored and compared to trends from complementary investigations, including collision cross-sections measured by drift tube ion mobility, reaction efficiency with ozone, and molecular dynamics simulations. Consistent trends across these modes of interrogation point to the importance of direct, through-space interactions between the charge site and the carbon-carbon double bond. Differences in the geometry and energetics of this intramolecular interaction underpin DMS separations and influence reactivity trends between regioisomers. Importantly, the disruption and reformation of these intramolecular solvation interactions during DMS are proposed to be the causative factor in the observed separations of ionized lipids which are shown to have otherwise identical collision cross-sections. These findings provide key insights into the strengths and limitations of current ion-mobility technologies for lipid isomer separations and can thus guide a more systematic approach to improved analytical separations in lipidomics.
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http://dx.doi.org/10.1021/acs.analchem.8b00469DOI Listing
April 2018

Clinical and metabolic consequences of L-serine supplementation in hereditary sensory and autonomic neuropathy type 1C.

Cold Spring Harb Mol Case Stud 2017 Nov 21;3(6). Epub 2017 Nov 21.

Research Programs Unit, Molecular Neurology, University of Helsinki, Helsinki 00014, Finland.

Hereditary sensory neuropathy type 1 (HSAN1) may be the first genetic neuropathy amenable to a specific mechanism-based treatment, as L-serine supplementation can be used to lower the neurotoxic levels of 1-deoxysphingolipids (1-deoxySL) that cause the neurodegeneration. The treatment is so far untested in HSAN1C caused by variants in the serine palmitoyl transferase subunit 2 () gene. The aim of this study was to establish whether oral L-serine lowers 1-deoxySL in a patient with HSAN1C, to perform a dose escalation to find the minimal effective dose, and to assess the safety profile and global metabolic effects of the treatment. Our patient underwent a 52-wk treatment in which the L-serine dose was titrated up to 400 mg/kg/day. She was followed up by repeated clinical examination, nerve conduction testing, and skin biopsies to document effects on small nerve fibers. Serum was assayed for 1-deoxySL and metabolomics analysis of 111 metabolites. We found a robust lowering of 1-deoxySL, which correlated in a near-linear fashion with increased serum L-serine levels. Metabolomics analysis showed a modest elevation in glycine and a marked reduction in the level of cytosine, whereas most of the other assayed metabolites did not change. There were no direct side effects from the treatment, but the patient developed a transitory toe ulceration during the course of the study. The Charcot-Marie-Tooth neuropathy score increased by 1 point. We conclude that oral supplementation of L-serine decreases 1-deoxySL in HSAN1C without major global effects on metabolism. L-serine is therefore a potential treatment for HSAN1C.
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http://dx.doi.org/10.1101/mcs.a002212DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5701299PMC
November 2017