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1.
Acta Diabetol ; 58(3): 319-327, 2021 Mar.
Article in English | MEDLINE | ID: mdl-33084982

ABSTRACT

BACKGROUND: Non-alcoholic fatty liver disease (NAFLD) is the most important cause of chronic liver disease in the western world. Steatosis can be accompanied by inflammation and cell damage (non-alcoholic steatohepatitis, NASH), and even liver fibrosis. Sphingolipids are a heterogeneous class of lipids and essential components of the plasma membrane and plasma lipoproteins. The atypical class of deoxy-sphingolipids has been implicated in the metabolic syndrome and type 2 diabetes. AIM: To determine if circulating (deoxy)sphingolipids are associated with NAFLD and its different entities, steatosis, inflammatory changes (inflammation and ballooning) and fibrosis. METHODS: Sphingolipids were analysed by LC-MS after hydrolysing the N-acyl and O-linked headgroups in plasma of obese adults who underwent a liver biopsy in suspicion of NAFLD. RESULTS: Two-hundred and eighty-eight patients were included. There was no association between typical sphingolipids and NAFLD and its different entities. There was a significant association between the presence of steatosis and the concentrations of deoxy-sphinganine [exp(B) 11.163 with CI (3.432, 36.306) and p < 0.001] and deoxy-sphingosine [exp(B) 8.486 with CI (3.437, 20.949) and p < 0.001]. There was no association between these deoxy-sphingolipids and activity of the steatohepatitis, nor was there any association with fibrosis. Differences in deoxy-sphingolipids also correlated independently with the presence of the metabolic syndrome, but not diabetes. CONCLUSION: Deoxy-sphingolipids are elevated in patients with steatosis compared to those without fatty liver, but not different between the different NAFLD subtypes, suggesting that deoxy-sphingolipid bases might be involved in steatogenesis, but not in the further progression of NAFLD to NASH nor in fibrogenesis.


Subject(s)
Fatty Liver/blood , Liver Cirrhosis/blood , Non-alcoholic Fatty Liver Disease/diagnosis , Non-alcoholic Fatty Liver Disease/pathology , Sphingolipids/blood , Adult , Belgium/epidemiology , Biopsy , Diabetes Mellitus, Type 2/blood , Diabetes Mellitus, Type 2/complications , Diabetes Mellitus, Type 2/epidemiology , Diabetes Mellitus, Type 2/pathology , Disease Progression , End Stage Liver Disease/blood , End Stage Liver Disease/diagnosis , End Stage Liver Disease/epidemiology , End Stage Liver Disease/pathology , Fatty Liver/diagnosis , Fatty Liver/epidemiology , Fatty Liver/pathology , Female , Humans , Liver/pathology , Liver Cirrhosis/diagnosis , Liver Cirrhosis/epidemiology , Liver Cirrhosis/pathology , Male , Middle Aged , Non-alcoholic Fatty Liver Disease/blood , Non-alcoholic Fatty Liver Disease/epidemiology , Obesity/blood , Obesity/complications , Obesity/epidemiology , Obesity/pathology , Prognosis
2.
Prog Lipid Res ; : 100995, 2019 Aug 21.
Article in English | MEDLINE | ID: mdl-31445071

ABSTRACT

Sphingoid bases encompass a group of long chain amino alcohols which form the essential structure of sphingolipids. Over the last years, these amphiphilic molecules were moving more and more into the focus of biomedical research due to their role as bioactive molecules. In fact, free sphingoid bases interact with specific receptors and target molecules and have been associated with numerous biological and physiological processes. In addition, they can modulate the biophysical properties of biological membranes. Several human diseases are related to pathological changes in the structure and metabolism of sphingoid bases. Yet, the mechanisms underlying their biological and pathophysiological actions remain elusive. Within this review, we aimed to summarize the current knowledge on the biochemical and biophysical properties of the most common sphingoid bases and to discuss their importance in health and disease.

3.
Prog Lipid Res ; 75: 100988, 2019 07.
Article in English | MEDLINE | ID: mdl-31132366

ABSTRACT

Sphingoid bases encompass a group of long chain amino alcohols which form the essential structure of sphingolipids. Over the last years, these amphiphilic molecules were moving more and more into the focus of biomedical research due to their role as bioactive molecules. In fact, free sphingoid bases interact with specific receptors and target molecules, and have been associated with numerous biological and physiological processes. In addition, they can modulate the biophysical properties of biological membranes. Several human diseases are related to pathological changes in the structure and metabolism of sphingoid bases. Yet, the mechanisms underlying their biological and pathophysiological actions remain elusive. Within this review, we aimed to summarize the current knowledge on the biochemical and biophysical properties of the most common sphingoid bases and to discuss their importance in health and disease.


Subject(s)
Sphingolipids/metabolism , Sphingosine/metabolism , Animals , Cell Membrane/metabolism , Humans , Molecular Structure , Sphingolipids/blood , Sphingolipids/chemistry , Sphingosine/blood , Sphingosine/chemistry
4.
Biochim Biophys Acta Mol Cell Biol Lipids ; 1864(4): 512-521, 2019 04.
Article in English | MEDLINE | ID: mdl-30625374

ABSTRACT

Sphingolipids (SLs) are fundamental components of eukaryotic cells. 1-Deoxysphingolipids differ structurally from canonical SLs as they lack the essential C1-OH group. Consequently, 1-deoxysphingolipids cannot be converted to complex sphingolipids and are not degraded over the canonical catabolic pathways. Pathologically elevated 1-deoxySLs are involved in several disease conditions. Within this review, we will provide an up-to-date overview on the metabolic, physiological and pathophysiological aspects of this enigmatic class of "headless" sphingolipids.


Subject(s)
Sphingolipids/chemistry , Sphingolipids/metabolism , Animals , Eukaryota/metabolism , Gene Regulatory Networks , Humans , Molecular Structure
5.
Bioorg Med Chem ; 26(14): 4047-4057, 2018 08 07.
Article in English | MEDLINE | ID: mdl-29960730

ABSTRACT

Sphingolipids are ubiquitous and abundant components of all eukaryotic and some prokaryotic organisms. Sphingolipids show a large structural variety not only between the different species, but also within an individual cell. This variety is not limited to alterations in the polar headgroups of e.g. glycosphingolipids, but also affects the lipophilic anchors comprised of different fatty acids on the one hand and different sphingoid bases on the other hand. The structural variations within different sphingoid bases e.g. in pathogens can be used to identify novel biomarkers and drug targets and the specific change in the profile of common and uncommon sphingolipids are associated with pathological conditions like diabetes or cancer. Therefore, the emerging field of sphingolipidomics is dedicated to collect data on the sphingolipidome of a cell and hence to assign changes therein to certain states of a cell or to pathological conditions. This powerful tool however is still limited by the availability of structural information about the individual lipid species as well as by the availability of appropriate internal standards for quantification. Herein we describe the synthesis of a variety of 1-deoxy-sphingoid bases. 1-DeoxySphingolipids have recently acquired significant attention due to its pathological role in the rare inherited neuropathy, HSAN1 but also as predictive biomarkers in diabetes type II. Some of the compounds synthesized and characterized herein, have been used and will be used to elucidate the correct structure of these disease-related lipids and their metabolites.


Subject(s)
Sphingosine/chemical synthesis , Biomarkers/chemistry , Biomarkers/metabolism , Diabetes Mellitus, Type 2/diagnosis , Diabetes Mellitus, Type 2/metabolism , Diabetes Mellitus, Type 2/pathology , Dose-Response Relationship, Drug , Humans , Molecular Conformation , Sphingosine/analogs & derivatives , Sphingosine/metabolism , Structure-Activity Relationship
6.
PLoS One ; 12(6): e0179313, 2017.
Article in English | MEDLINE | ID: mdl-28582468

ABSTRACT

[This corrects the article DOI: 10.1371/journal.pone.0175776.].

7.
PLoS One ; 12(5): e0175776, 2017.
Article in English | MEDLINE | ID: mdl-28472035

ABSTRACT

1-Deoxysphingolipids (1-deoxySLs) are atypical sphingolipids, which are formed in a side reaction during sphingolipid de-novo synthesis. Recently, we demonstrated that 1-deoxySLs are biomarkers for the prediction of T2DM in obese, non-diabetic patients. Here we investigated the relevance of 1-deoxySLs as long-term predictive biomarkers for the incidence of T2DM in an asymptomatic population. Here, we analyzed the plasma sphingoid base profile in a nested group of non-diabetic individuals (N = 605) selected from a population-based study including 5 year follow-up data (CoLaus study). 1-DeoxySLs at baseline were significantly elevated in individuals who developed T2DM during the follow-up (p<0.001), together with increased glucose (p<5.11E-14), triglycerides (p<0.001) and HOMA-IR indices (p<0.001). 1-Deoxy-sphinganine (1-deoxySA) and 1-deoxy-sphingosine (1-deoxySO) were predictive for T2DM, even after adjusting for fasting glucose levels in the binary regression analyses. The predictive value of the combined markers 1-deoxySA+glucose were superior to glucose alone in normal-weight subjects (p<0.001) but decreased substantially with increasing BMI. Instead, plasma adiponectin and waist-to-hip ratio appeared to be better risk predictors for obese individuals (BMI>30kg/m2). In conclusion, elevated plasma 1-deoxySL levels are strong and independent risk predictors of future T2DM, especially for non-obese individuals in the general population.


Subject(s)
Biomarkers/blood , Diabetes Mellitus, Type 2/blood , Sphingolipids/blood , Aged , Blood Glucose/metabolism , Female , Humans , Male , Middle Aged
8.
Eur J Neurol ; 22(5): 806-14, e55, 2015 May.
Article in English | MEDLINE | ID: mdl-25623782

ABSTRACT

BACKGROUND AND PURPOSE: Diabetic distal sensorimotor polyneuropathy (DSPN) is a frequent, disabling complication of diabetes mellitus. There is increasing evidence that sphingolipids play a role in insulin resistance and type 2 diabetes (T2DM). Whether neurotoxic 1-deoxy-sphingolipids are elevated in DSPN patients' plasma and whether levels correlate to the DSPN stage were examined. METHODS: The plasma profile of 12 sphingoid bases in patients with DSPN and T2DM(n = 39) were cross-sectionally compared to other nerve disorders including chronic inflammatory demyelinating polyneuropathy (CIDP) (n = 13), transthyretin-related familial amyloid polyneuropathy (FAP) (n = 10), amyotrophic lateral sclerosis (ALS) (n = 13) and small fibre neuropathy (n = 12) by liquid chromatography mass spectrometry. Correlations to the DSPN stage were additionally performed. Furthermore, the sphingoid base distribution in sural nerve specimens was measured in patients with DSPN (n = 6) compared to CIDP (n = 3). RESULTS: A significantly increased amount of 1-deoxy-sphingolipids [1-deoxy-sphinganine (0.11 ± 0.06 µmol/l), 1-deoxy-sphingosine (0.24 ± 0.16 µmol/l)] in patients with DSPN was observed compared to age-matched healthy controls (0.06 ± 0.03 µmol/l; 0.12 ± 0.05 µmol/l) and to the other groups. (Para)clinical parameters including sensory loss, neuropathic pain, weakness, vibration perception, nerve conduction velocity, sensory nerve action potentials (sural nerve) and duration of T2DM did not correlate with plasma 1-deoxy-sphingolipid levels, neither did the clinical stage according to the Dyck classification for DSPN. Sphingolipid levels in sural nerve biopsies showed no differences between DSPN and CIDP. Contrarily, patients with a small fibre neuropathy had decreased C20-sphingosine plasma levels. CONCLUSION: 1-deoxy-sphingolipid plasma levels are significantly elevated in DSPN. They are already detectable in early disease stages but do not correlate with the clinical course. Further knowledge on 1-deoxy-sphingolipids might lead to a better pathophysiological understanding and future treatment options in DSPN.


Subject(s)
Amyotrophic Lateral Sclerosis/blood , Diabetes Mellitus, Type 2/blood , Diabetic Neuropathies/blood , Erythromelalgia/blood , Polyneuropathies/blood , Sphingolipids/blood , Adult , Aged , Disease Susceptibility , Female , Humans , Male , Middle Aged
10.
Cell Death Dis ; 3: e280, 2012 Mar 15.
Article in English | MEDLINE | ID: mdl-22419109

ABSTRACT

Triacylglycerol (TG) accumulation caused by adipose triglyceride lipase (ATGL) deficiency or very low-density lipoprotein (VLDL) loading of wild-type (Wt) macrophages results in mitochondrial-mediated apoptosis. This phenotype is correlated to depletion of Ca(2+) from the endoplasmic reticulum (ER), an event known to induce the unfolded protein response (UPR). Here, we show that ER stress in TG-rich macrophages activates the UPR, resulting in increased abundance of the chaperone GRP78/BiP, the induction of pancreatic ER kinase-like ER kinase, phosphorylation and activation of eukaryotic translation initiation factor 2A, the translocation of activating transcription factor (ATF)4 and ATF6 to the nucleus and the induction of the cell death executor CCAAT/enhancer-binding protein homologous protein. C16:0 ceramide concentrations were increased in Atgl-/- and VLDL-loaded Wt macrophages. Overexpression of ceramide synthases was sufficient to induce mitochondrial apoptosis in Wt macrophages. In accordance, inhibition of ceramide synthases in Atgl-/- macrophages by fumonisin B1 (FB1) resulted in specific inhibition of C16:0 ceramide, whereas intracellular TG concentrations remained high. Although the UPR was still activated in Atgl-/- macrophages, FB1 treatment rescued Atgl-/- macrophages from mitochondrial dysfunction and programmed cell death. We conclude that C16:0 ceramide elicits apoptosis in Atgl-/- macrophages by activation of the mitochondrial apoptosis pathway.


Subject(s)
Apoptosis/drug effects , Ceramides/metabolism , Macrophages/metabolism , Mitochondria/metabolism , Signal Transduction/drug effects , Triglycerides/pharmacology , Activating Transcription Factor 4/metabolism , Activating Transcription Factor 6/metabolism , Animals , CCAAT-Enhancer-Binding Proteins/metabolism , Calcium/deficiency , Endoplasmic Reticulum/drug effects , Endoplasmic Reticulum/metabolism , Endoplasmic Reticulum Chaperone BiP , Enzyme Inhibitors/pharmacology , Fumonisins/pharmacology , Heat-Shock Proteins/metabolism , Humans , Lipase/antagonists & inhibitors , Lipase/deficiency , Lipoproteins, VLDL/metabolism , Macrophages/cytology , Macrophages/drug effects , Male , Mice , Mice, Knockout , Mitochondria/drug effects , Triglycerides/metabolism , Unfolded Protein Response/drug effects
11.
Diabetologia ; 55(2): 421-31, 2012 Feb.
Article in English | MEDLINE | ID: mdl-22124606

ABSTRACT

AIMS/HYPOTHESIS: Sphingolipid synthesis is typically initiated by the conjugation of L-serine and palmitoyl-CoA, a reaction catalysed by serine palmitoyltransferase (SPT). SPT can also metabolise other acyl-CoAs (C(12) to C(18)) and other amino acids such as L-alanine and glycine, giving rise to a spectrum of atypical sphingolipids. Here, we aimed to identify changes in plasma levels of these atypical sphingolipids to explore their potential as biomarkers in the metabolic syndrome and diabetes. METHODS: We compared the plasma profiles of ten sphingoid bases in healthy individuals with those of patients with the metabolic syndrome but not diabetes, and diabetic patients (n = 25 per group). The results were verified in a streptozotocin (STZ) rat model. Univariate and multivariate statistical analyses were used. RESULTS: Deoxysphingolipids (dSLs) were significantly elevated (p = 5 × 10⁻6) in patients with the metabolic syndrome (0.11 ± 0.04 µmol/l) compared with controls (0.06 ± 0.02 µmol/l) but did not differ between the metabolic syndrome and diabetes groups. Levels of C(16)-sphingosine-based sphingolipids were significantly lowered in diabetic patients but not in patients with the metabolic syndrome but without diabetes (p = 0.008). Significantly elevated dSL levels were also found in the plasma and liver of STZ rats. A principal component analysis revealed a similar or even closer association of dSLs with diabetes and the metabolic syndrome in comparison with the established biomarkers. CONCLUSIONS/INTERPRETATION: We showed that dSLs are significantly elevated in patients with type 2 diabetes mellitus and non-diabetic metabolic syndrome compared with healthy controls. They may, therefore, be useful novel biomarkers to improve risk prediction and therapy monitoring in these patients.


Subject(s)
Biomarkers/blood , Diabetes Mellitus, Type 2/blood , Metabolic Syndrome/blood , Serine C-Palmitoyltransferase/blood , Sphingolipids/blood , Aged , Animals , Biomarkers/metabolism , Catalysis , Cohort Studies , Diabetes Mellitus, Type 2/diagnosis , Disease Models, Animal , Female , Humans , Male , Middle Aged , Multivariate Analysis , Principal Component Analysis , Rats , Risk , Streptozocin/pharmacology
12.
Biochim Biophys Acta ; 1480(1-2): 365-73, 2000 Jul 14.
Article in English | MEDLINE | ID: mdl-10899637

ABSTRACT

The dimeric chicken brain type isoenzyme of creatine kinase (BB-CK) was mutated by a C283S amino acid exchange in the catalytic site to produce a basically inactive dimer (B*B*-CK). The mutated enzyme showed a residual activity of about 4% compared to the wild-type, whereas substrate binding parameters were not altered. The inactivated dimer was hybridized with native dimeric muscle enzyme (MM-CK) to produce a partially inactivated MB*-CK heterodimeric hybrid and also to a his-tagged BB-CK (hBhB-CK) resulting in a partially inactive hBB*-CK homodimer. The generated hybrids were purified by chromatography. The V(max) and substrate binding parameters K(m) and K(d) were determined for both directions of the CK reaction and compared to the parameters of the wild-type enzymes (MM-, BB-, hBhB-, MB-CK). In the direction of ATP synthesis (reverse reaction), the MB*- and hBB*-CK hybrids showed a decrease of V(max) to 34% and 32%, respectively, compared to the unmodified wild-type isoform. The inactivation of a single subunit in MB*-CK led to an increase in the K(d) value resulting in an significant substrate synergism, not seen with the MB-CK wild-type enzyme. In the direction of phosphocreatine synthesis (forward reaction), the modified hybrids showed a decrease of V(max) to 50% of the wild-type enzymes and no significant alterations of the K(m) and K(d) parameters. These results strongly suggest an enzymatic cooperativity of the two subunits in the reverse reaction but independent catalytic function in the forward reaction.


Subject(s)
Creatine Kinase/chemistry , Animals , Chickens , Creatine Kinase/genetics , Dimerization , Kinetics , Mutagenesis, Site-Directed
13.
J Cell Biol ; 149(6): 1225-34, 2000 Jun 12.
Article in English | MEDLINE | ID: mdl-10851020

ABSTRACT

Creatine kinase (CK) is located in an isoenzyme-specific manner at subcellular sites of energy production and consumption. In muscle cells, the muscle-type CK isoform (MM-CK) specifically interacts with the sarcomeric M-line, while the highly homologous brain-type CK isoform (BB-CK) does not share this property. Sequence comparison revealed two pairs of lysine residues that are highly conserved in M-CK but are not present in B-CK. The role of these lysines in mediating M-line interaction was tested with a set of M-CK and B-CK point mutants and chimeras. We found that all four lysine residues are involved in the isoenzyme-specific M-line interaction, acting pair-wise as strong (K104/K115) and weak interaction sites (K8/K24). An exchange of these lysines in MM-CK led to a loss of M-line binding, whereas the introduction of the very same lysines into BB-CK led to a gain of function by transforming BB-CK into a fully competent M-line-binding protein. The role of the four lysines in MM-CK is discussed within the context of the recently solved x-ray structures of MM-CK and BB-CK.


Subject(s)
Creatine Kinase/metabolism , Lysine/chemistry , Psoas Muscles/enzymology , Sarcomeres/metabolism , Amino Acid Sequence , Animals , Creatine Kinase/genetics , Fluorescent Antibody Technique , Isoenzymes , Lysine/genetics , Models, Molecular , Molecular Sequence Data , Mutagenesis, Site-Directed , Protein Binding , Rabbits , Recombinant Fusion Proteins/genetics , Sequence Homology, Amino Acid
14.
J Muscle Res Cell Motil ; 21(7): 691-703, 2000.
Article in English | MEDLINE | ID: mdl-11227796

ABSTRACT

The specific interaction of muscle type creatine-kinase (MM-CK) with the myofibrillar M-line was demonstrated by exchanging endogenous MM-CK with an excess of fluorescently labeled MM-CK in situ, using chemically skinned skeletal muscle fibers and confocal microscopy. No binding of labeled MM-CK was noticed at the I-band of skinned fibers, where the enzyme is additionally located in vivo, as shown earlier by immunofluorescence staining of cryosections of intact muscle. However, when rhodamine-labeled MM-CK was diffused into skinned fibers that had been preincubated with phosphofructokinase (PFK), a glycolytic enzyme known to bind to actin, a striking in vivo-like interaction of Rh-MM-CK with the I-band was found, presumably mediated by binding of Rh-MM-CK to the glycolytic enzyme. Aldolase, another actin-binding glycolytic enzyme was also able to bind Rh-MM-CK to the I-band, but formation of the complex occurred preferably at long sarcomere length (> 3.0 microm). Neither pyruvate kinase, although known for its binding to actin, nor phosphoglycerate kinase (PGK), not directly interacting with the I-band itself, did mediate I-band targeting of MM-CK. Anchoring of MM-CK to the I-band via PFK, but not so via aldolase, was strongly pH-dependent and occurred below pH 7.0. Labeling performed at different sarcomere length indicated that the PFK/MM-CK complex bound to thin filaments of the I-band, but not within the actomyosin overlap zones. The physiological consequences of the structural interaction of MM-CK with PFK at the I-band is discussed with respect to functional coupling of MM-CK to glycolysis, metabolic regulation and channeling in multi-enzyme complexes. The in situ binding assay with skinned skeletal muscle fibers described here represents a useful method for further studies of specific protein-protein interactions in a structurally intact contractile system under various precisely controlled conditions.


Subject(s)
Creatine Kinase/metabolism , Muscle, Skeletal/metabolism , Animals , Creatine Kinase/ultrastructure , Fructose-Bisphosphate Aldolase , Microscopy, Confocal , Muscle, Skeletal/ultrastructure , Phosphofructokinase-1 , Phosphoglycerate Kinase , Pyruvate Kinase , Rabbits , Sarcomeres/metabolism , Sarcomeres/ultrastructure
16.
Biofactors ; 8(3-4): 229-34, 1998.
Article in English | MEDLINE | ID: mdl-9914824

ABSTRACT

Creatine kinase (CK) isoenzymes, specifically located at places of energy demand and energy production, are linked by a phosphocreatine/creatine (PCr/Cr) circuit, found in cells with intermittently high energy demands. Cytosolic CKs, in close conjunction with Ca(2+)-pumps, play a crucial role for the energetics of Ca(2+)-homeostasis. Mitochondrial Mi-CK, a cuboidal-shaped octamer with a central channel, binds and crosslinks mitochondrial membranes and forms a functionally coupled microcompartment with porin and adenine nucleotide translocase for vectorial export of PCr into the cytosol. The CK system is regulated by AMP-activated protein kinase via PCr/Cr and ATP/AMP ratios. Mi-CK stabilizes and cross-links cristae- or inner/outer membranes to form parallel membrane stacks and, if overexpressed due to creatine depletion or cellular energy stress, forms those crystalline intramitochondrial inclusions seen in some mitochondrial cytopathy patients. Mi-CK is a prime target for free radical damage by peroxynitrite. Mi-CK octamers, together with CK substrates have a marked stabilizing and protective effect against mitochondrial permeability transition pore opening, thus providing a rationale for creatine supplementation of patients with neuromuscular and neurodegenerative diseases.


Subject(s)
Creatine Kinase/chemistry , Creatine Kinase/physiology , Energy Metabolism , Mitochondria/enzymology , Adenine Nucleotides/metabolism , Animals , Calcium/metabolism , Cytosol/enzymology , Humans , Isoenzymes , Mitochondria/physiology , Phosphocreatine/metabolism
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