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Enhanced plasma levels of NEFA have been shown to induce hepatic insulin resistance, which contributes to the development of type 2 diabetes. Indeed, sphingolipids can be formed via a de novo pathway from the saturated fatty acid palmitate and the amino acid serine. Besides ceramides, sphingosine 1-phosphate (S1P) has been identified as a major bioactive lipid mediator. Therefore, our aim was to investigate the generation and function of S1P in hepatic insulin resistance.
The incorporation of palmitate into sphingolipids was performed by rapid-resolution liquid chromatography-MS/MS in primary human and rat hepatocytes. The influence of S1P and the involvement of S1P receptors in hepatic insulin resistance was examined in human and rat hepatocytes, as well as in New Zealand obese (NZO) mice.
Palmitate induced an impressive formation of extra- and intracellular S1P in rat and human hepatocytes. An elevation of hepatic S1P levels was observed in NZO mice fed a high-fat diet. Once generated, S1P was able, similarly to palmitate, to counteract insulin signalling. The inhibitory effect of S1P was abolished in the presence of the S1P(2) receptor antagonist JTE-013 both in vitro and in vivo. In agreement with this, the immunomodulator FTY720-phosphate, which binds to all S1P receptors except S1P(2), was not able to inhibit insulin signalling.
These data indicate that palmitate is metabolised by hepatocytes to S1P, which acts via stimulation of the S1P(2) receptor to impair insulin signalling. In particular, S1P(2) inhibition could be considered as a novel therapeutic target for the treatment of insulin resistance.
Insulin resistance is a complex metabolic disorder in which insulin-sensitive tissues fail to respond to the physiological action of insulin. There is a strong correlation of insulin resistance and the development of type 2 diabetes both reaching epidemic proportions. Dysfunctional lipid metabolism is a hallmark of insulin resistance and a risk factor for several cardiovascular and metabolic disorders. Numerous studies in humans and rodents have shown that insulin resistance is associated with elevations of non-esterified fatty acids (NEFA) in the plasma. Moreover, bioactive lipid intermediates such as diacylglycerol (DAG) and ceramides appear to accumulate in response to NEFA, which may interact with insulin signaling. However, recent work has also indicated that sphingosine 1-phosphate (S1P), a breakdown product of ceramide, modulate insulin signaling in different cell types. In this review, we summarize the current state of knowledge about S1P and insulin signaling in insulin sensitive cells. A specific focus is put on the action of S1P on hepatocytes, pancreatic beta-cells and skeletal muscle cells. In particular, modulation of S1P-signaling can be considered as a potential therapeutic target for the treatment of insulin resistance and type 2 diabetes.
The use of silver nanoparticles in medical and consumer products such as wound dressings, clothing and cosmetic has increased significantly in recent years. Still, the influence of these particles on our health and especially on our brain, has not been examined adequately up to now. We studied the influence of AgEO- (Ethylene Oxide) and AgCitrate-Nanoparticles (NPs) on the protective barriers of the brain, namely the blood-brain barrier (BBB) and the blood-cerebrospinal fluid (blood-CSF) barrier in vitro. The NPs toxicity was evaluated by examining changes in membrane integrity, cell morphology, barrier properties, oxidative stress and inflammatory reactions. AgNPs decreased cell viability, disturbed barrier integrity and tight junctions and triggered oxidative stress and DNA strand breaks. However, all mentioned effects were, at least partly, suppressed by a Citrate-coating and were most pronounced in the cells of the BBB as compared to the epithelial cells representing the blood-CSF barrier. AgEO- but not AgCitrate-NPs also triggered an inflammatory reaction in porcine brain capillary endothelial cells (PBCEC), which represent the BBB.
Our data indicate that AgNPs may cause adverse effects within the barriers of the brain, but their toxicity can be reduced by choosing an appropriate coating material.
The toxicologically most relevant mercury (Hg) species for human exposure is methylmercury (MeHg). Thiomersal is a common preservative used in some vaccine formulations. The aim of this study is to get further mechanistic insight into the yet not fully understood neurotoxic modes of action of organic Hg species. Mercury species investigated include MeHgCl and thiomersal. Additionally HgCl2 was studied, since in the brain mercuric Hg can be formed by dealkylation of the organic species. As a cellular system astrocytes were used. In vivo astrocytes provide the environment necessary for neuronal function. In the present study, cytotoxic effects of the respective mercuricals increased with rising alkylation level and correlated with their cellular bioavailability. Further experiments revealed for all species at subcytotoxic concentrations no induction of DNA strand breaks, whereas all species massively increased H2O2-induced DNA strand breaks. This co- genotoxic effect is likely due to a disturbance of the cellular DNA damage response. Thus, at nanomolar, sub-cytotoxic concentrations, all three mercury species strongly disturbed poly(ADP-ribosyl)ation, a signalling reaction induced by DNA strand breaks. Interestingly, the molecular mechanism behind this inhibition seems to be different for the species. Since chronic PARP-1 inhibition is also discussed to sacrifice neurogenesis and learning abilities, further experiments on neurons and in vivo studies could be helpful to clarify whether the inhibition of poly(ADP-ribosyl) ation contributes to organic Hg induced neurotoxicity.
Context: Relations between fibroblast growth factor-23 (FGF-23), soluble alpha-klotho (s-alpha-klotho), and kidney function in chronic kidney disease (CKD) are still unclear. Especially the role of s-alpha-klotho requires further study.
Objectives: Our objectives were to analyze the relation of s-alpha-klotho to estimated glomerular filtration rate (eGFR), FGF-23, and other parameters of calcium-phosphate metabolism and to investigate the response of s-alpha-klotho to cholecalciferol.
Patients, Design, and Setting: Twenty-four CKD (stage 1-5) patients participated in this 8-week randomized controlled trial (vitamin D and chronic renal insufficiency).
Interventions: Interventions included 40 000 IU cholecalciferol or placebo weekly.
Main Outcome Measure: S-alpha-klotho was determined by ELISA with antihuman klotho antibodies 67G3 and 91F1.
Results: For all patients, s-alpha-klotho concentrations did not differ between CKD stages. When patients were subdivided based on FGF-23 concentrations, a positive association of s-alpha-klotho with eGFR became apparent in patients with lower than median FGF-23 concentrations but not in those above median value. Patients with s-alpha-klotho below 204 pg/mL showed higher age, lower phosphate clearance, and lower bone-specific alkaline phosphatase compared with patients with higher s-alpha-klotho. Treatment with cholecalciferol significantly increased 1,25-dihydroxyvitamin D. The increase of FGF-23 had only borderline significance. There was no significant effect of high-dose cholecalciferol administration for 8 weeks on plasma s-alpha-klotho.
Conclusions: CKD patients with s-alpha-klotho below 204 pg/mL had higher age, lower phosphate clearance, and lower bone-specific alkaline phosphatase. An association of s-alpha-klotho with eGFR was observed only in the presence of close to normal, but not high, FGF-23 concentrations. Cholecalciferol treatment did not change s-alpha-klotho concentrations.