Affect Sphingolipid Metabolism Research Articles

Alterations in sphingolipid synthesis during training, detraining, and retraining may alter myogenesis in skeletal muscle

The benefits of exercise on metabolic health and its effectiveness at reducing morbidity risk are well established. Exercise training enhances skeletal muscle metabolism and function, but whether such adaptations persist through detraining and how they are potentiated with retraining are not well understood. Recent evidence has highlighted the role sphingolipids play on skeletal muscle size and function, but how exercise affects sphingolipid metabolism is not yet known. We hypothesize that alterations in skeletal muscle sphingolipid metabolism with exercise training are necessary to enhance muscle mass with further exercise retraining. Here, mice were SEDentary (SED; static cages) or exercise-TRAINed (TRAIN; voluntary wheel running) and chow-fed. We performed body composition analysis (using EchoMRI) and skeletal muscle collection [tibialis anterior ( TA), extensor digitorum longus ( EDL), gastrocnemius ( Gas), Soleus ( Sol), plantaris ( Plant), and levator ani ( LA)] following training (4wks), detraining (8wk), and retraining (12wk) in three independent cohorts. Sphingolipid and myogenic gene expression was measured in TA muscle by qPCR. Exercise training concomitantly increased lean and decreased fat percentage ( p<0.05), while increasing Sol muscle mass in TRAIN mice ( p<0.05), compared to SED. This was accompanied by higher sphingolipid metabolism ( Acer1, p<0.05; and Cers1, p=0.058) and myogenic gene expression ( MyoD, Myf5; p<0.05). Following detraining, TRAIN mice had an overall increase in lean-to-fat mass ( p<0.05) while maintaining all individual muscle masses ( p<0.05), compared to SED. This was accompanied by a reduction in gene expression of the sphingolipid receptor S1pr1 and myogenic factor Myf5 ( p<0.05), but no differences in sphingolipid metabolism ( Acer1, Cers1). Lastly, retraining increased lean and decreased fat percentage ( p<0.05) and enhanced the masses of TA, Gas, Sol, and Plant muscles in TRAIN mice ( p<0.05), compared to SED. This was accompanied by a reduced expression of rate limiting sphingolipid synthesis genes Sptlc1 and Sptlc2 and the kinase Sphk1 ( p<0.05), but no differences in Cers1 or myogenic gene expression in TRAIN mice, compared to SED. Overall, our data shows that exercise training and retraining potentiate muscle mass accretion and dynamically regulates sphingolipid metabolism adaptations. These data suggest a potential role for sphingolipids to modulate long-lasting improvements to skeletal muscle. Funding was provided by the University of Illinois Urbana-Champaign. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Pharmacodynamics and mechanism of Erigeron breviscapus granules in the treatment of ischemic stroke in mice by regulating sphingolipid metabolism based on metabolomics

AimErigeron breviscapus (Vant.) Hand.-Mazz. (EB) granules is the extract preparation of EB, with clear curative effect and unclear mechanism. This study intends to systematically explore the specific mechanism of EB granules in the treatment of IS from the metabolic perspective. MethodsThe model of transient middle cerebral artery occlusion (tMCAO) in mice was established by the suture-occluded method. The therapeutic effect of EB granules on tMCAO mice was evaluated by behavioral evaluation, brain water content determination, 2,3,5-triphenyltetrazolium chloride (TTC) staining, hematoxylin-eosin (HE) staining, and levels of lactate dehydrogenase (LDH) and neuron specific enolase (NSE) in serum. In order to screen differential metabolites, non-targeted metabolomics technology was used to detect the metabolites in serum before and after administration. Univariate statistics, multivariate statistics and bioinformatics were used to analyze the changes of metabolites in serum of tMCAO mice. The possible related mechanism of EB granules in treating IS was screened by pathway enrichment analysis, and the preliminary verification was carried out at animal level by enzyme linked immunosorbent assay (ELISA) and western blot (WB). ResultsEB granules could significantly improve behavior of tMCAO mice, reduce brain water content and cerebral infarction volume, improve morphology of brain tissue, reduce the levels of LDH and NSE in serum. A total of 232 differential metabolites were screened, which were mainly enriched in many biological processes such as sphingolipid metabolism. The differential metabolite S1P and its receptors S1PR1 and S1PR2 in sphingolipid metabolism were verified. The results showed that the level of S1P in brain tissue increased and the protein expression of S1PR1 decreased significantly after modeling, and reversed after administration, but there was no significant difference in the protein expression of S1PR2. ConclusionThe therapeutic effects of EB granules may be related to affecting sphingolipid metabolism through regulating S1P/S1PR1.

Chronic Cerebral Hypoperfusion Aggravates Parkinson's Disease Dementia-Like Symptoms and Pathology in 6-OHDA-Lesioned Rat through Interfering with Sphingolipid Metabolism.

Chronic cerebral hypoperfusion (CCH) is a cardinal risk factor for Parkinson's disease dementia (PDD), but this potential causality lacks mechanistic evidence. We selected bilateral common carotid artery occlusion (BCCAO) to simulate chronic cerebral hypoperfusion in the rat model of PD induced by typical neurotoxin 6-hydroxy dopamine (6-OHDA). Four weeks after unilateral injection of 6-OHDA into the medial forebrain bundle, rats underwent BCCAO. Male Sprague-Dawley rats were divided into five groups of ten, including sham, PD+BCCAO 2 weeks, PD+BCCAO 1 week, PD, and BCCAO 2 weeks. Then, open field test (OFT) and Morris water maze test (MWM) were used to assess the PDD-like symptoms in rats. Also, the pathological manifestations and mechanisms of BCCAO impairing cognitive functions have been explored via hematoxylin-eosin staining, Nissl staining, immunohistochemistry, immunofluorescence, RNA sequencing analysis, lipidomics, and quantitative real-time polymerase chain reaction. In this study, we found that CCH could aggravate PDD-like cognitive symptoms (i.e., learning memory and spatial cognition) and PDD-like pathology (higher expression of α-Syn and Aβ in prefrontal cortex and striatum). Moreover, a potential relationship between differentially expressed mRNAs and lipid metabolism was revealed by RNA sequencing analysis. Lipidomics showed that CCH could affect the intensity of 5 lipids, including sphingomyelin (SM 9:0;2O/26:2; SM 8:1;2O/25:0; and SM 8:0;2O/28:4), cardiolipin, lysophosphatidylcholine, cholesteryl ester, and triacylglycerol. Interestingly, the KEGG pathway analysis of both RNA sequencing analysis and lipidomics suggested that CCH leaded to learning impairment by affecting sphingolipid metabolism. Finally, we found that CCH disrupts the sphingolipid metabolism by affecting the mRNA expression of SMPD1 and SMS2, leading to the accumulation of sphingomyelin in the prefrontal cortex. In summary, CCH, an independent exacerbating reason for impairment in learning and memory within the pathopoiesis of PD, aggravates Parkinson's disease dementia-like symptoms and pathology in 6-OHDA-lesioned rat through interfering with sphingolipid metabolism.

GOLM1 depletion modifies cellular sphingolipid metabolism and adversely affects cell growth

Golgi membrane protein 1 (GOLM1) is a Golgi-resident type 2 transmembrane protein known to be overexpressed in several cancers, including hepatocellular carcinoma (HCC), as well as in viral infections. However, the role of GOLM1 in lipid metabolism remains enigmatic. In this study, we employed siRNA-mediated GOLM1 depletion in Huh-7 HCC cells to study the role of GOLM1 in lipid metabolism. Mass spectrometric lipidomic analysis in GOLM1 knockdown cells showed an aberrant accumulation of sphingolipids, such as ceramides, hexosylceramides, dihexosylceramides, sphinganine, sphingosine, and ceramide phosphate, along with cholesteryl esters. Furthermore, we observed a reduction in phosphatidylethanolamines and lysophosphatidylethanolamines. In addition, Seahorse extracellular flux analysis indicated a reduction in mitochondrial oxygen consumption rate upon GOLM1 depletion. Finally, alterations in Golgi structure and distribution were observed both by electron microscopy imaging and immunofluorescence microscopy analysis. Importantly, we found that GOLM1 depletion also affected cell proliferation and cell cycle progression in Huh-7 HCC cells. The Golgi structural defects induced by GOLM1 reduction might potentially affect the trafficking of proteins and lipids leading to distorted intracellular lipid homeostasis, which may result in organelle dysfunction and altered cell growth. In conclusion, we demonstrate that GOLM1 depletion affects sphingolipid metabolism, mitochondrial function, Golgi structure, and proliferation of HCC cells.

Arabidopsis alkaline ceramidase ACER functions in defense against insect herbivory.

Plant sphingolipids are important membrane components and bioactive molecules in development and defense responses. However, the function of sphingolipids in plant defense, especially against herbivores, is not fully understood. Here, we report that Spodoptera exigua feeding affects sphingolipid metabolism in Arabidopsis, resulting in increased levels of sphingoid long-chain bases, ceramides, and hydroxyceramides. Insect-induced ceramide and hydroxyceramide accumulation is dependent on the jasmonate signaling pathway. Loss of the Arabidopsis alkaline ceramidase ACER increases ceramides and decreases long-chain base levels in plants; in this work, we found that loss of ACER enhances plant resistance to S. exigua and improves response to mechanical wounding. Moreover, acer-1 mutants exhibited more severe root-growth inhibition and higher anthocyanin accumulation than wild-type plants in response to methyl jasmonate treatment, indicating that loss of ACER increases sensitivity to jasmonate and that ACER functions in jasmonate-mediated root growth and secondary metabolism. Transcript levels of ACER were also negatively regulated by jasmonates, and this process involves the transcription factor MYC2. Thus, our findings reveal that ACER is involved in mediating jasmonate-related plant growth and defense and that jasmonates function in regulating the expression of ACER.

Polychlorinated environmental toxicants affect sphingolipid metabolism during neurogenesis in vitro

Sphingolipids (SLs) are important signaling molecules and functional components of cellular membranes. Although SLs are known as crucial regulators of neural cell physiology and differentiation, modulations of SLs by environmental neurotoxicants in neural cells and their neuronal progeny have not yet been explored. In this study, we used in vitro models of differentiated neuron-like cells, which were repeatedly exposed during differentiation to model environmental toxicants, and we analyzed changes in sphingolipidome, cellular morphology and gene expression related to SL metabolism or neuronal differentiation. We compared these data with the results obtained in undifferentiated neural cells with progenitor-like features. As model polychlorinated organic pollutants, we used 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), 3,3′-dichlorobiphenyl (PCB11) and 2,2′,4,4′,5,5′-hexachlorobiphenyl (PCB153). PCB153 revealed itself as the most prominent deregulator of SL metabolism and as potent toxicant during early phases of in vitro neurogenesis. TCDD exerted only minor changes in the levels of analysed lipid species, however, it significantly changed the rate of pro-neuronal differentiation and deregulated expression of neuronal markers during neurogenesis. PCB11 acted as a potent disruptor of in vitro neurogenesis, which induced significant alterations in SL metabolism and cellular morphology in both differentiated neuron-like models (differentiated NE4C and NG108-15 cells). We identified ceramide-1-phosphate, lactosylceramides and several glycosphingolipids to be the most sensitive SL species to exposure to polychlorinated pollutants. Additionally, we identified deregulation of several genes related to SL metabolism, which may be explored in future as potential markers of developmental neurotoxicity.

Cannabidiol – A phytocannabinoid that widely affects sphingolipid metabolism under conditions of brain insulin resistance

Obesity-related insulin resistance (IR) and attenuated brain insulin signaling are significant risk factors for neurodegenerative disorders, e.g., Alzheimer’s disease. IR and type 2 diabetes correlate with an increased concentration of sphingolipids, a class of lipids that play an essential structural role in cellular membranes and cell signaling pathways. Cannabidiol (CBD) is a nonpsychoactive constituent of Cannabis sativa plant that interacts with the endocannabinoidome. Despite known positive effects of CBD on improvement in diabetes and its aftermath, e.g., anti-inflammatory and anti-oxidant effects, there are no studies evaluating the effect of phytocannabinoids on the brain insulin resistance and sphingolipid metabolism. Our experiment was carried out on Wistar rats that received a high-fat diet and/or intraperitoneal CBD injections. In our study, we indicated inhibition of de novo synthesis and salvage pathways, which resulted in significant changes in the concentration of sphingolipids, e.g., ceramide and sphingomyelin. Furthermore, we observed reduced brain IR and decreased tau protein phosphorylation what might be protective against neuropathologies development. We believe that our research will concern a new possible therapeutic approach with Cannabis -plant derived compounds and within a few years, cannabinoids would be considered as prominent substances for targeting both metabolic and neurodegenerative pathologies.

Sphingosine 1- Phosphate Lyase Insufficiency Syndrome (SPLIS); A Role in Multiple Endocrinopathies

Sphingosine 1-phosphate lyase insufficiency syndrome (SPLIS) was described in 2017 as a novel condition affecting sphingolipid metabolism. There is a multisystemic phenotype including nephrotic syndrome and primary adrenal insufficiency (PAI) and to a lesser extent ichthyosis, neurological disease and lymphopenia. A proportion of patients also presented with hypothyroidism and hypogonadism. To interrogate the endocrine aspect of the syndrome we reviewed clinical data within our patient cohort with SPLIS and those within the wider literature. To date there have been 45 patients identified with SPLIS with significant associated mortality (n=23/45, 51%; 4 of these in utero). There is no clear genotype-phenotype correlation. Whilst nephrotic syndrome is most prevalent (n=34/45; 76%), a significant proportion of patients (n=27/45, 60%) also presented with glucocorticoid deficiency, some with additional mineralocorticoid deficiency (n=7/27). Five further patients were noted to have adrenal calcifications though biochemistry was not undertaken. Most patients presented with PAI in the first 2 years of life (n=21/27), with the oldest presentation being 11 years of age. Adrenal calcifications are a common finding in those who had documented imaging (n=13/15, 87%). Primary gonadal failure has been reported in 8 male cases, all with concomitant PAI. Presenting features included microphallus (n=7/8) and cryptorchidism (n=8/8), indicating reduced in utero androgen exposure. All who had biochemical evaluation demonstrated raised basal LH and FSH/ exaggerated response to LHRH stimulation, a lack of testosterone response to HCG stimulation and low antimullerian hormone (AMH) levels. To date there are no reports of pubertal delay in female patients, and those of age within our cohort have normal ovarian reserve as evidenced by AMH levels (n=2). Primary hypothyroidism, with mildly raised TSH and low Free T4 is reported in 12 patients. Most did not have goiters and had concomitant PAI and nephrotic syndrome (n=11/12). SPLIS is unique amongst sphingolipid disorders in presenting with significant endocrinopathy. This may be the consequence of the particular sphingolipid signature of the disease and the pathogenic mechanisms need to be explored further. It is clear that endocrine dysfunction needs to be considered at diagnosis and surveillance undertaken to detect evolving disease which could have a significant impact on morbidity and mortality.

The effect of enterolactone on sphingolipid pathway and hepatic insulin resistance development in HepG2 cells

AimsObesity and type 2 diabetes mellitus, correlate with increased tissue concentration of sphingolipids, which directly interfere with insulin signaling pathway. Phytoestrogens are a group of plant-derived compounds that have been studied in the case of metabolic disorders treatment. Therefore, the aim of this study was to ascertain whether enterolactone (ENL), a commonly known phytoestrogen, may affect sphingolipid metabolism and decrease hepatic insulin resistance development in a lipid overload state. Main methodsThe study was conducted on HepG2 cells incubated with ENL and/or palmitic acid (PA) for 16 h. Intra- and extracellular sphingolipid concentrations were assessed by high performance liquid chromatography. The expression of sphingolipid pathway enzymes, apoptosis and insulin signaling pathway proteins and glucose metabolism regulators were evaluated by Western Blot. Key findingsIn HepG2 cells, a considerable augmentation of intracellular ceramide and sphingosine concentration in ENL with PA group were indicated with simultaneous increase in extracellular ceramide concentration. The ENL treatment increased expression of selected enzymes from de novo ceramide synthesis pathway with lower expression of ceramide transfer protein. We also observed a decreased expression of insulin-stimulated phosphorylation of AKT and AMPK after exposure to ENL with PA. Our research demonstrated that ENL with PA resulted in an increased expression of caspase-3. SignificanceEnterolactone, in a higher fatty acids availability, led to the development of hepatic IR in HepG2 cells. This phenomenon may be the result of elevated intracellular ceramide accumulation caused by increased de novo synthesis pathway what led to enhanced apoptosis of HepG2 cells.

A systematic simulation of the effect of salicylic acid on sphingolipid metabolism.

The phytohormone salicylic acid (SA) affects plant development and defense responses. Recent studies revealed that SA also participates in the regulation of sphingolipid metabolism, but the details of this regulation remain to beexplored. Here, we use in silico Flux Balance Analysis (FBA) with published microarray data to construct a whole-cell simulation model, including 23 pathways, 259 reactions, and 172 metabolites, to predict the alterations in flux of major sphingolipid species after treatment with exogenous SA. This model predicts significant changes in fluxes of certain sphingolipid species after SA treatment, changes that likely trigger downstream physiological and phenotypic effects. To validate the simulation, we used 15N-labeled metabolic turnover analysis to measure sphingolipid contents and turnover rate in Arabidopsis thaliana seedlings treated with SA or the SA analog benzothiadiazole (BTH). The results show that both SA and BTH affect sphingolipid metabolism, altering the concentrations of certain species and also changing the optimal flux distribution and turnover rate of sphingolipids. Our strategy allows us to estimate sphingolipid fluxes on a short time scale and gives us a systemic view of the effect of SA on sphingolipid homeostasis.

A sphingosine kinase inhibitor combined with temozolomide induces glioblastoma cell death through accumulation of dihydrosphingosine and dihydroceramide, endoplasmic reticulum stress and autophagy.

Glioblastomas (GBMs) are very aggressive tumors with low chemosensitivity. The DNA-alkylating agent temozolomide (TMZ) is currently the most efficient chemotoxic drug for GBM therapy; however, many patients develop resistance to TMZ. Combining TMZ with another agent could present an improved treatment option if it could overcome TMZ resistance and avoid side effects. Sphingosine kinase inhibitors (SKIs) have emerged as anticancer agents. Sphingosine kinases are often overexpressed in tumors where their activity of phosphorylating sphingosine (Sph) contributes to tumor growth and migration. They control the levels of the pro-apoptotic ceramide (Cer) and Sph and of the pro-survival sphingosine-1 phosphate. In the present work, TMZ was combined with a specific SKI, and the cytotoxic effect of each drug alone or in combination was tested on GBM cell lines. The combination of sublethal doses of both agents resulted in the cell death potentiation of GBM cell lines without affecting astrocyte viability. It triggered a caspase-3-dependent cell death that was preceded by accumulation of dihydrosphingosine (dhSph) and dihydroceramide (dhCer), oxidative stress, endoplasmic reticulum stress, and autophagy. Autophagy was identified as the crucial switch that facilitated induction of this cell death potentiation. The sublethal dose of the inhibitor induced these stress events, whereas that of TMZ induced the destructive autophagy switch. Remarkably, neither Cer nor Sph, but rather the Cer intermediates, dhSph and dhCer, was involved in the cytotoxicity from the combination. Cell lines sensitive to the combination expressed low levels of the antioxidant enzyme glutathione peroxidase-1, indicating this enzyme as a potential marker of sensitivity to such treatment. This work shows for the first time a strong interaction between a SKI and TMZ, leading to a tumor cell-specific death induction. It further demonstrates the biological relevance of dihydrosphingolipids in cell death mechanisms and emphasizes the potential of drugs that affect sphingolipid metabolism for cancer therapy.

Loss of ceramide kinase in Arabidopsis impairs defenses and promotes ceramide accumulation and mitochondrial H2O2 bursts.

Arabidopsis thaliana plants that lack ceramide kinase, encoded by ACCELERATED CELL DEATH5 (ACD5), display spontaneous programmed cell death late in development and accumulate substrates of ACD5. Here, we compared ceramide accumulation kinetics, defense responses, ultrastructural features, and sites of reactive oxygen species (ROS) production in wild-type and acd5 plants during development and/or Botrytis cinerea infection. Quantitative sphingolipid profiling indicated that ceramide accumulation in acd5 paralleled the appearance of spontaneous cell death, and it was accompanied by autophagy and mitochondrial ROS accumulation. Plants lacking ACD5 differed significantly from the wild type in their responses to B. cinerea, showing earlier and higher increases in ceramides, greater disease, smaller cell wall appositions (papillae), reduced callose deposition and apoplastic ROS, and increased mitochondrial ROS. Together, these data show that ceramide kinase greatly affects sphingolipid metabolism and the site of ROS accumulation during development and infection, which likely explains the developmental and infection-related cell death phenotypes. The acd5 plants also showed an early defect in restricting B. cinerea germination and growth, which occurred prior to the onset of cell death. This early defect in B. cinerea restriction in acd5 points to a role for ceramide phosphate and/or the balance of ceramides in mediating early antifungal responses that are independent of cell death.

C282Y-HFE Gene Variant Affects Cholesterol Metabolism in Human Neuroblastoma Cells

Although disruptions in the maintenance of iron and cholesterol metabolism have been implicated in several cancers, the association between variants in the HFE gene that is associated with cellular iron uptake and cholesterol metabolism has not been studied. The C282Y-HFE variant is a risk factor for different cancers, is known to affect sphingolipid metabolism, and to result in increased cellular iron uptake. The effect of this variant on cholesterol metabolism and its possible relevance to cancer phenotype was investigated using wild type (WT) and C282Y-HFE transfected human neuroblastoma SH-SY5Y cells. Expression of C282Y-HFE in SH-SY5Y cells resulted in a significant increase in total cholesterol as well as increased transcription of a number of genes involved in its metabolism compared to cells expressing WT-HFE. The marked increase in expression of NPC1L1 relative to that of most other genes, was accompanied by a significant increase in expression of NPC1, a protein that functions in cholesterol uptake by cells. Because inhibitors of cholesterol metabolism have been proposed to be beneficial for treating certain cancers, their effect on the viability of C282Y-HFE neuroblastoma cells was ascertained. C282Y-HFE cells were significantly more sensitive than WT-HFE cells to U18666A, an inhibitor of desmosterol Δ24-reductase the enzyme catalyzing the last step in cholesterol biosynthesis. This was not seen for simvastatin, ezetimibe, or a sphingosine kinase inhibitor. These studies indicate that cancers presenting in carriers of the C282Y-HFE allele might be responsive to treatment designed to selectively reduce cholesterol content in their tumor cells.

Inhibition of GM3 synthase attenuates neuropathology of Niemann-Pick disease Type C. by affecting sphingolipid metabolism.

In several lysosomal storage disorders, including Niemann-Pick disease Type C (NP-C), sphingolipids, including glycosphingolipids, particularly gangliosides, are the predominant storage materials in the brain, raising the possibility that accumulation of these lipids may be involved in the NP-C neurodegenerative process. However, correlation of these accumulations and NP-C neuropathology has not been fully characterized. Here we derived NP-C mice with complete and partial deletion of the Siat9 (encoding GM3 synthase) gene in order to investigate the role of ganglioside in NP-C pathogenesis. According to our results, NPC mice with homozygotic deletion of GM3 synthase exhibited an enhanced neuropathological phenotype and died significantly earlier than NP-C mice. Notably, in contrast to complete depletion, NP-C mice with partial deletion of the GM3 synthase gene showed ameliorated NP-C neuropathology, including motor disability, demyelination, and abnormal accumulation of cholesterol and sphingolipids. These findings indicate the crucial role of GM3 synthesis in the NP-C phenotype and progression of CNS pathologic abnormality, suggesting that well-controlled inhibition of GM3 synthesis could be used as a therapeutic strategy.

Farber disease: understanding a fatal childhood disorder and dissecting ceramide biology

Farber disease: understanding a fatal childhood disorder and dissecting ceramide biology

Structure, Signalling and Physiologic Role of Adiponectin-Dietary and Exercise- Related Variations

Since its discovery in 1995 adiponectin has garnered considerable interest from the academic, clinical and biotech communities due to its proposed salutary anti-inflammatory, anti-diabetic, anti-atherogenic and cardioprotective properties. As a result our appreciation of adiponectin's structure and the importance of post-translational modifications (PTMs) in adiponectin production are now relatively advanced. So too, following the identification of a variety of adiponectin receptors, binding proteins and downstream signalling networks, is our understanding of adiponectin's intracellular signalling pathways that are implicated in mediating adiponectin's pleiotropic effects. Adiponectin's ability to moderate inflammation, which is recognised as a key protagonist in many modern diseases, may be the key to many of its beneficial effects. Recent insights indicate that adiponectin modulates cellular inflammation by affecting sphingolipid metabolism, with the adiponectin receptors displaying intrinsic ceramidase activity. In the current review we will summarise the molecular details of adiponectin, discuss key players and recent insights into adiponectin signalling and consider the physiologic role(s) of adiponectin. We will also review studies into the effects of diet or exercise on circulating adiponectin levels focusing largely on reports from human trials.

Linoleic acid supplement in cystic fibrosis: friend or foe?

Linoleic acid supplement in cystic fibrosis: friend or foe?

Sphingolipidomics: a valuable tool for understanding the roles of sphingolipids in biology and disease

The sphingolipidome is the portion of the lipidome that encompasses all sphingoid bases and their derivatives. Whereas the most studied sphingoid base is sphingosine [(2S,3R,4E)-2-aminooctadecene-1,3-diol], mammals have dozens of structural variants, and hundreds of additional types have been found in other eukaryotic organisms and some bacteria and viruses. Multiplying these figures by the N-acyl-derivatives ("ceramides") and the more than 500 phospho- and glyco- headgroups places the number of discrete molecular species in the tens of thousands or higher. Structure-specific, quantitative information about a growing fraction of the sphingolipidome can now be obtained using various types of chromatography coupled with tandem mass spectrometry, and application of these methods is producing many surprises regarding sphingolipid structure, metabolism, and function. Such large data sets can be difficult to interpret, but the development of tools that display results from genomic and lipidomic studies in a pathway relational, nodal, context can make it easier for investigators to deal with this complexity.

Sphingolipids Function as Downstream Effectors of a Fungal PAQR

The Izh2p protein from Saccharomyces cerevisiae belongs to the newly characterized progestin and adipoQ receptor (PAQR) superfamily of receptors whose mechanism of signal transduction is still unknown. Izh2p functions as a receptor for the plant PR-5 defensin osmotin and has pleiotropic effects on cellular biochemistry. One example of this pleiotropy is the Izh2p-dependent repression of FET3, a gene involved in iron-uptake. Although the physiological purpose of FET3 repression by Izh2p is a matter of speculation, it provides a reporter with which to probe the mechanism of signal transduction by this novel class of receptor. Receptors in the PAQR family share sequence similarity with enzymes involved in ceramide metabolism, which led to the hypothesis that sphingolipids are involved in Izh2p-dependent signaling. In this study, we demonstrate that drugs affecting sphingolipid metabolism, such as d-erythro-MAPP and myriocin, inhibit the effect of Izh2p on FET3. We also show that Izh2p causes an increase in steady-state levels of sphingoid base. Moreover, we show that Izh2p-independent increases in sphingoid bases recapitulate the effect of Izh2p on FET3. Finally, our data indicate that the Pkh1p and Pkh2p sphingoid base-sensing kinases are essential components of the Izh2p-dependent signaling pathway. In conclusion, our data indicate that Izh2p produces sphingoid bases and that these bioactive lipids probably function as the second messenger responsible for the effect of Izh2p on FET3.

Effects of flavonoids on sphingolipid turnover in the toxin-damaged liver and liver cells.

BackgroundThe ceramide generation is an early event in the apoptotic response to numerous stimuli including the oxidative stress and ceramide analogs mimic the stress effect and induce apoptosis. Flavonoids of German chamomile are reported to exhibit the hepatoprotective effect. Flavonoids affect sphingolipid metabolism and reduce the elevated ceramide level in the aged liver. In the present paper, the ceramide content and production in the CCl4- and ethanol-treated liver and hepatocytes as well as the correction of sphingolipid metabolism in the damaged liver using the mixture of German chamomile flavonoids (chamiloflan) or apigenin-7-glucoside (AP7Glu) have been investigated.ResultsThe experiments were performed in either the rat liver or hepatocytes of normal, CCl4- and ethanol-treated or flavonoid- and toxin plus flavonoid-treated animals. [14C]palmitic acid and [methyl-14C-phosphorylcholine]sphingomyelin were used to investigate the sphingolipid turnover. Addition of the CCl4 or ethanol to isolated hepatocyte suspensions caused loss of cell viability and increased the lactate dehydrogenase release from the cells into supernatant and ceramide level in the cells. CCl4 administration to the rats enlarged ceramide mass as well as neutral sphingomyelinase (SMase) activity and reduced ceramide degradation by the neutral ceramidase. Pretreatment of isolated hepatocytes with flavonoids abrogated the CCl4 effects on the cell membrane integrity and normalized the ceramide content. Flavonoid administration to the rats normalized the elevated ceramide content in the damaged liver via neutral SMase inhibition and ceramidase activation.ConclusionThe data obtained have demonstrated that flavonoids affect sphingolipid metabolism in the CCl4- and ethanol-damaged liver and liver cells. Flavonoids normalized activities of key enzymes of sphingolipid turnover (neutral SMase and ceramidase) and ceramide contents in the damaged liver and liver cells, and stabilized the hepatocyte membranes.