sphingosine-1-phosphate and Fatty-Liver

Over 20 years ago, sphingosine-1-phosphate (S1P) was discovered to be a bioactive signaling molecule. Subsequent studies later identified two related kinases, sphingosine kinase 1 and 2, which are responsible for the phosphorylation of sphingosine to S1P. Many stimuli increase sphingosine kinase activity and S1P production and secretion. Outside the cell, S1P can bind to and activate five S1P-specific G protein-coupled receptors (S1PR1-5) to regulate many important cellular and physiological processes in an autocrine or paracrine manner. S1P is found in high concentrations in the blood where it functions to control vascular integrity and trafficking of lymphocytes. Obesity increases blood S1P levels in humans and mice. With the world wide increase in obesity linked to consumption of high-fat, high-sugar diets, S1P is emerging as an accomplice in liver pathobiology, including acute liver failure, metabolic syndrome, control of blood lipid and glucose homeostasis, nonalcoholic fatty liver disease, and liver fibrosis. Here, we review recent research on the importance of sphingosine kinases, S1P, and S1PRs in liver pathobiology, with a focus on exciting insights for new therapeutic modalities that target S1P signaling axes for a variety of liver diseases.

Topics: Animals; Fatty Liver; Humans; Liver; Liver Diseases; Liver Failure; Lysophospholipids; Metabolic Syndrome; Phosphotransferases (Alcohol Group Acceptor); Sphingosine

Sphingolipids, especially ceramide and S1P, are structural components of biological membranes and bioactive molecules which participate in diverse cellular activities such as cell division, differentiation, gene expression and apoptosis. Emerging evidence demonstrates the role of sphingolipids in hepatocellular death, which contributes to the progression of several liver diseases including ischaemia-reperfusion liver injury, steatohepatitis or hepatocarcinogenesis. Furthermore, some data indicate that the accumulation of some sphingolipids contributes to the hepatic dysfunctions. Hence, understanding of sphingolipid may open up a novel therapeutic avenue to liver diseases. This review focuses on the progress in the sphingolipid metabolic pathway with a focus on hepatic diseases and drugs targeting the sphingolipid pathway.

Topics: Apoptosis; Ceramides; Fatty Liver; Humans; Liver Diseases; Lysophospholipids; Reperfusion Injury; Sphingolipids; Sphingosine

Adiponectin has received considerable attention for its potential anti-diabetic actions. The adipokine exerts control of glucose and lipid homeostasis via critical effects within the liver, adipose, and pancreas. By stimulating adipogenesis, opposing inflammation, and influencing rates of lipid oxidation and lipolysis, adiponectin critically governs lipid spillover into non-adipose tissues. Ceramide, a cytotoxic and insulin desensitizing lipid metabolite formed when peripheral tissues are exposed to excessive lipid deposition, is potently opposed by adiponectin. Via adiponectin receptors, AdipoR1 and AdipoR2, adiponectin stimulates the deacylation of ceramide- yielding sphingosine for conversion to sphingosine 1-phosphate (S1P) by sphingosine kinase. The resulting conversion from ceramide to S1P promotes survival of functional beta cell mass, allowing for insulin production to meet insulin demands. Alleviation of ceramide burden on the liver allows for improvements in hepatic insulin action. Here, we summarize how adiponectin-induced changes in these tissues lead to improvements in glucose metabolism, highlighting the sphingolipid signaling mechanisms linking adiponectin to each action. ONE SENTENCE SUMMARY: We review the anti-diabetic actions of adiponectin.

Topics: Adipocytes; Adiponectin; Adipose Tissue; Animals; Apoptosis; Cell Proliferation; Ceramides; Down-Regulation; Fatty Liver; Glucose; Hepatocytes; Humans; Insulin Resistance; Insulin-Secreting Cells; Lipid Metabolism; Liver; Lysophospholipids; Mice; Sphingosine; Thiazolidines

Sphingosine-1-phosphate (S1P) is a bioactive sphingolipid that interacts via 5 G-protein coupled receptors, S1PR1-5, to regulate signalling pathways critical to biological processes including cell growth, immune cell trafficking, and inflammation.We demonstrate that in Type 2 diabetic (T2D) subjects, plasma S1P levels significantly increased in response to the anti-diabetic drug, rosiglitazone, and, S1P levels correlated positively with measures of improved glucose homeostasis. In HFD-induced obese C57BL/6 J mice S1PR3 gene expression was increased in adipose tissues (AT) and liver compared with low fat diet (LFD)-fed counterparts. On a HFD, weight gain was similar in both S1PR3-/- mice and WT littermates; however, HFD-fed S1PR3-/- mice exhibited a phenotype of partial lipodystrophy, exacerbated insulin resistance and glucose intolerance. This worsened metabolic phenotype of HFD-fed S1PR3-/- mice was mechanistically linked with increased adipose inflammation, adipose macrophage and T-cell accumulation, hepatic inflammation and hepatic steatosis. In 3T3-L1 preadipocytes S1P increased adipogenesis and S1P-S1PR3 signalling regulated the expression of PPARγ, suggesting a novel role for this signalling pathway in the adipogenic program. These results reveal an anti-diabetic role for S1P, and, that S1P-S1PR3 signalling in the adipose and liver defends against excessive inflammation and steatosis to maintain metabolic homeostasis at key regulatory pathways.

Topics: Animals; Biological Phenomena; Diet, High-Fat; Fatty Liver; Humans; Inflammation; Lysophospholipids; Mice; Mice, Inbred C57BL; Obesity; Sphingosine; Sphingosine-1-Phosphate Receptors

Monocyte chemotactic protein-1 (MCP-1) is one of the most representative inflammatory cytokines, and has been proved to be markedly increased in injured liver and sphingosine 1-phosphate (S1P)-treated macrophages. However, microRNAs (miRNAs) targeting MCP-1 and the role of miRNA/MCP-1 axis in S1P-mediated liver inflammation remain largely unknown. Here, we demonstrate that MCP-1 expression is increased in the liver and isolated liver macrophages of MCDHF mice. Moreover, there is a positive correlation between the hepatic levels of S1P and MCP-1. We then predict miRNAs targeting MCP-1 by bioinformatics analysis and select miRNA-1249-5p (miR-1249-5p) from the intersection of TargetScan database and downregulated miRNAs in the injured liver. S1P significantly upregulates the expression of MCP-1 and decreases miR-1249-5p expression in macrophages. MiR-1249-5p directly targets 3'-UTR of MCP-1 and negatively regulates its expression in S1P-treated macrophages. Administration of miR-1249-5p agomir decreases hepatic MCP-1 levels and attenuates liver inflammation in MCDHF mice. Protein-protein interaction network by STRING displays that S1P system is closely associated with MCP-1/CCR2 axis in the network of inflammation. In conclusion, we characterize the vital role of miR-1249-5p in negatively regulating MCP-1 expression in vitro and in vivo, which may open new perspectives for pharmacological treatment of liver disease.

Topics: 3' Untranslated Regions; Animals; Chemokine CCL2; Disease Models, Animal; Fatty Liver; Inflammation; Liver; Lysophospholipids; Macrophages; Mice; MicroRNAs; Sphingosine

Sphingomyelin synthase 2 (SMS2) regulates sphingomyelin synthesis and contributes to obesity and hepatic steatosis. Here, we investigated the effect of SMS2 deficiency on liver fibrosis in mice fed with choline-deficient, L-amino acid-defined, high-fat diet (CDAHFD) or injected with carbon tetrachloride (CCl

Topics: Amino Acids; Animals; Chemical and Drug Induced Liver Injury; Choline; Diet, High-Fat; Fatty Liver; Liver; Liver Cirrhosis; Lysophospholipids; Mice, Knockout; Signal Transduction; Sphingosine; Transferases (Other Substituted Phosphate Groups)

Sphingolipid metabolites have emerged playing important roles in the pathogenesis of nonalcoholic fatty liver disease, whereas the underlying mechanism remains largely unknown. In the present study, we provide both in vitro and in vivo evidence showing a pathogenic role of sphingosine kinase 1 (SphK1) in hepatocellular steatosis. We found that levels of SphK1 expression were significantly increased in steatotic hepatocytes. Enforced overexpression of SphK1 or treatment with sphingosine 1-phosphate (S1P) markedly enhanced hepatic lipid accumulation. In contrast, the siRNA-mediated knockdown of SphK1 or S1P receptors, S1P2 and S1P3, profoundly inhibited lipid accumulation in hepatocytes. Moreover, Sphk1(-/-) mice exhibited a significant amelioration of hepatosteatosis under diet-induced obese (DIO) conditions, compared to wild-type littermates. In addition, DIO-induced up-regulation of PPARγ and its target genes were significantly reduced by SphK1 deficiency. Furthermore, treatment of hepatocytes with S1P induces a dose-dependent increase in PPARγ expression at the transcriptional level. Blockage of S1P receptors and the Akt-mTOR signaling profoundly inhibited S1P-induced PPARγ expression. Notably, down-regulation of PPARγ by using its siRNA significantly diminished the pro-steatotic effect of SphK1/S1P. Thus, the study demonstrates a new pathway connecting SphK1 and PPARγ involved in the pathogenesis of hepatocellular steatosis.

Topics: Animals; Diet, High-Fat; Dietary Fats; Fatty Liver; Gene Expression Regulation; Hepatocytes; Lysophospholipids; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Mice, Obese; Obesity; Phosphotransferases (Alcohol Group Acceptor); PPAR gamma; Proto-Oncogene Proteins c-akt; Receptors, Lysosphingolipid; RNA, Small Interfering; Signal Transduction; Sphingosine; Sphingosine-1-Phosphate Receptors; TOR Serine-Threonine Kinases; Transcription, Genetic

The endoplasmic reticulum (ER) is the principal organelle in the cell for protein folding and trafficking, lipid synthesis, and cellular calcium homeostasis. Perturbation of ER function results in activation of the unfolded protein response (UPR) and is implicated in abnormal lipid biosynthesis and development of insulin resistance. In this study, we investigated whether transcription of sphingosine kinase (Sphk)2 is regulated by ER stress-mediated UPR pathways. Sphk2, a major isotype of sphingosine kinase in the liver, was transcriptionally up-regulated by tunicamycin and lipopolysaccharides. Transcriptional regulation of Sphk2 was mediated by activation of activating transcription factor (ATF)4 as demonstrated by promoter assays, immunoblotting, and small interfering RNA analyses. In primary hepatocytes, adenoviral Sphk2 expression elevated cellular sphingosine 1 phosphate (S1P) and activated protein kinase B phosphorylation, with no alteration of insulin receptor substrate phosphorylation. Hepatic overexpression of Sphk2 in mice fed a high-fat diet (HFD) led to elevated S1P and reduced ceramide, sphingomyelin, and glucosylceramide in plasma and liver. Hepatic accumulation of lipid droplets by HFD feeding was reduced by Sphk2-mediated up-regulation of fatty acid (FA) oxidizing genes and increased FA oxidation in liver. In addition, glucose intolerance and insulin resistance were ameliorated by improved hepatic insulin signaling through Sphk2 up-regulation.. Sphk2 is transcriptionally up-regulated by acute ER stress through activation of ATF4 and improves perturbed hepatic glucose and FA metabolism.

Topics: Activating Transcription Factor 4; Animals; Cells, Cultured; Diet, High-Fat; Endoplasmic Reticulum Stress; Fatty Acids; Fatty Liver; Hepatocytes; Insulin Resistance; Lipid Droplets; Lipids; Liver; Lysophospholipids; Male; Mice, Inbred C57BL; Oxidation-Reduction; Phosphotransferases (Alcohol Group Acceptor); Proto-Oncogene Proteins c-akt; Sphingosine; Unfolded Protein Response; Up-Regulation

Sphingosine 1-phosphate (S1P)/S1P receptor (S1PR) system has been implicated in the pathological process of liver injury. This study was designed to evaluate the effects of S1P/S1PR on bone marrow-derived monocyte/macrophage (BMM) migration in mouse models of cholestatic liver injury, and identify the signaling pathway underlying this process. S1PR1-3 expression in BMM was characterized by immunofluorescence, RT-PCR and Western blot. Cell migration was determined in Boyden chambers. In vivo, the chimera mice, which received BM transplants from EGFP-transgenic mice, received an operation of bile duct ligation (BDL) to induce liver injury with the administration of S1PR2/3 antagonists. The results showed that S1PR1-3 were all expressed in BMMs. S1P exerted a powerful migratory action on BMMs via S1PR2 and S1PR3. Furthermore, PTX and LY-294002 (PI3K inhibitor) prevented S1PR2/3-mediated BMM migration, and Rac1 activation by S1P was inhibited by JTE-013, CAY-10444 or LY294002. Administration of S1PR2/3 antagonists in vivo significantly reduced BMM recruitment in BDL-treated mice, and attenuated hepatic inflammation and fibrosis. In conclusion, S1P/S1PR2/3 system mediates BMM motility by PTX-PI3K-Rac1 signaling pathway, which provides new compelling information on the role of S1P/S1PR in liver injury and opens new perspectives for the pharmacological treatment of hepatic fibrosis.

Topics: Animals; Bone Marrow Cells; Cell Movement; Cells, Cultured; Chemokines; Chromones; Cytokines; Enzyme-Linked Immunosorbent Assay; Fatty Liver; Fibrosis; Liver; Lysophospholipids; Macrophages; Mice; Mice, Inbred ICR; Mice, Transgenic; Microscopy, Fluorescence; Morpholines; Neuropeptides; Phosphatidylinositol 3-Kinases; Phosphoinositide-3 Kinase Inhibitors; Pyrazoles; Pyridines; rac1 GTP-Binding Protein; Real-Time Polymerase Chain Reaction; Receptors, Lysosphingolipid; RNA Interference; RNA, Small Interfering; Signal Transduction; Sphingosine; Sphingosine-1-Phosphate Receptors

Steatosis is a risk factor in partial hepatectomy (PH) under ischaemia-reperfusion (I/R), which is commonly applied in clinical practice to reduce bleeding. Nutritional support strategies, as well as the role of peripheral adipose tissue as energy source for liver regeneration, remain poorly investigated.. To investigate whether the administration of either glucose or a lipid emulsion could protect steatotic and non-steatotic livers against damage and regenerative failure in an experimental model of PH under I/R. The relevance of peripheral adipose tissue in liver regeneration following surgery is studied.. Steatotic and non-steatotic rat livers were subjected to surgery and the effects of either glucose or lipid treatment on damage and regeneration, and part of the underlying mechanisms, were investigated.. In non-steatotic livers, treatment with lipids or glucose provided the same protection against damage, regeneration failure and ATP drop. Adipose tissue was not required to regenerate non-steatotic livers. In the presence of hepatic steatosis, lipid treatment, but not glucose, protected against damage and regenerative failure by induction of cell cycle, maintenance of ATP levels and elevation of sphingosine-1-phosphate/ceramide ratio and phospholipid levels. Peripheral adipose tissue was required for regenerating the steatotic liver but it was not used as an energy source.. Lipid treatment in non-steatotic livers provides the same protection as that afforded by glucose in conditions of PH under I/R, whereas the treatment with lipids is preferable to reduce the injurious effects of liver surgery in the presence of steatosis.

Topics: Adenosine Triphosphate; Analysis of Variance; Animals; Ceramides; Fatty Liver; Glucose; Hepatectomy; Ischemia; Lipids; Liver; Lysophospholipids; Rats; Regeneration; Reperfusion; Sphingosine