sphingosine-1-phosphate and Chemical-and-Drug-Induced-Liver-Injury

Until recently, all approved multiple sclerosis (MS) disease treatments were administered parenterally. Oral fingolimod was approved in September 2010 by the US Food and Drug Administration to reduce relapses and disability progression in relapsing forms of MS. In the clinical trials that led to approval, fingolimod reduced not only acute relapses and magnetic resonance imaging lesion activity but also disability progression and brain volume loss, suggesting preservation of tissue. Fingolimod's mechanism of action in MS is not known with certainty. Its active form, fingolimod-phosphate (fingolimod-P), is a sphingosine 1-phosphate receptor (S1PR) modulator that inhibits egress of lymphocytes from lymph nodes and their recirculation, potentially reducing trafficking of pathogenic cells into the central nervous system (CNS). Fingolimod also readily penetrates the CNS, and fingolimod-P formed in situ may have direct effects on neural cells. Fingolimod potently inhibits the MS animal model, experimental autoimmune encephalomyelitis, but is ineffective in mice with selective deficiency of the S1P₁ S1PR subtype on astrocytes despite normal expression in the immune compartment. These findings suggest that S1PR modulation by fingolimod in both the immune system and CNS, producing a combination of beneficial anti-inflammatory and possibly neuroprotective/reparative effects, may contribute to its efficacy in MS. In clinical trials, fingolimod was generally safe and well tolerated. Its interaction with S1PRs in a variety of tissues largely accounts for the reported adverse effects, which were seen more frequently with doses 2.5 to 10x the approved 0.5 mg dose. Fingolimod's unique mechanism of action distinguishes it from all other currently approved MS therapies.

Topics: Animals; Central Nervous System; Chemical and Drug Induced Liver Injury; Clinical Trials as Topic; Disease Models, Animal; Fingolimod Hydrochloride; Heart Diseases; Humans; Immunosuppressive Agents; Infections; Liver Diseases; Lymphocytes; Lysophospholipids; Multiple Sclerosis; Propylene Glycols; Receptors, Lysosphingolipid; Respiration Disorders; 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)

Activities of sphingomyelinase and ceramidase decreased in the liver in chronic toxic hepatitis and the balance between the levels of proapoptotic ceramide and antiapoptotic sphyngosine-1-phosphate shifts towards the latter substance. Pronounced changes in the qualitative and quantitative composition of fatty acids in the sphingomyelin cycle effector molecules were revealed.

Topics: Animals; Ceramidases; Ceramides; Chemical and Drug Induced Liver Injury; Hepatitis, Chronic; Liver; Lysophospholipids; Male; Rats; Sphingomyelin Phosphodiesterase; Sphingomyelins; Sphingosine

Fumonisin B(1), a mycotoxin, is an inhibitor of ceramide synthase causing marked dysregulation of sphingolipid metabolism in cells. This mycotoxin causes accumulation of free sphingoid bases (sphingosine and dihydrosphingosine or sphinganine) and their metabolites, important messengers involved in signal transduction leading to either cell survival or death. Free sphingoid bases are known apoptotic molecules whereas sphingosine 1-phosphate is protective. We previously reported that fumonisin B(1) caused sphingosine kinase (SPHK) induction along with the increase of serine palmitoyltransferase (SPT). Fumonisin B(1) also increased inducible nitric oxide synthase (iNOS) expression. In the current study we employed a mouse strain with the targeted deletion of iNOS gene (Nos-KO) to evaluate the role of nitric oxide (NO) on fumonisin B(1)-induced hepatotoxicity. The Nos-KO mice exhibited increased hepatotoxicity after subacute fumonisin B(1) exposure compared to their wild type counterparts, the liver regeneration was lower in Nos-KO compared to that in the WT mice. Increased hepatotoxicity in Nos-KO was not related to the extent of free sphingoid base accumulation after fumonisin B(1) treatment; however, it was accompanied by a lack of fumonisin B(1)-induced SPHK induction. The fumonisin B(1)-induced SPT was unaffected by lack of iNOS gene. Deletion of iNOS gene did not prevent fumonisin B(1)-dependent induction of inflammatory cytokines, namely tumor necrosis factor alpha, interferon gamma and interleukin-12. The lack of fumonisin B(1)-induced SPHK induction in Nos-KO was supported by a similar effect on phosphorylated metabolites of sphingoid bases; the equilibrium between sphingoid bases and their phosphates is maintained by SPHK. We therefore conclude that iNOS induction produced by fumonisin B(1) modulates SPHK activity; the lack of iNOS prevents generation of sphingosine 1-phosphate and deprives cells from its protective effects.

Topics: Alanine Transaminase; Animals; Aspartate Aminotransferases; Carcinogens, Environmental; Cell Proliferation; Chemical and Drug Induced Liver Injury; Fumonisins; Hepatocytes; In Situ Nick-End Labeling; Interferon-gamma; Interleukin-12; Liver Diseases; Liver Regeneration; Lysophospholipids; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Nitric Oxide; Nitric Oxide Synthase Type II; Phosphotransferases (Alcohol Group Acceptor); RNA, Messenger; Sphingosine; Tumor Necrosis Factor-alpha; Weight Loss

Sphingosine 1-phosphate (S1P) is a bioactive sphingolipid produced by sphingosine kinase (SphK1 and 2). We previously showed that S1P receptors (S1P1, S1P2, and S1P3) are expressed in hepatic myofibroblasts (hMF), a population of cells that triggers matrix remodeling during liver injury. Here we investigated the function of these receptors in the wound healing response to acute liver injury elicited by carbon tetrachloride, a process that associates hepatocyte proliferation and matrix remodeling. Acute liver injury was associated with the induction of S1P2, S1P3, SphK1, and SphK2 mRNAs and increased SphK activity, with no change in S1P1 expression. Necrosis, inflammation, and hepatocyte regeneration were similar in S1P2-/- and wild-type (WT) mice. However, compared with WT mice, S1P2-/- mice displayed reduced accumulation of hMF, as shown by lower induction of smooth muscle alpha-actin mRNA and lower induction of TIMP-1, TGF-beta1, and PDGF-BB mRNAs, overall reflecting reduced activation of remodeling in response to liver injury. The wound healing response was similar in S1P3-/- and WT mice. In vitro, S1P enhanced proliferation of cultured WT hMF, and PDGF-BB further enhanced the mitogenic effect of S1P. In keeping with these findings, PDGF-BB up-regulated S1P2 and SphK1 mRNAs, increased SphK activity, and S1P2 induced PDGF-BB mRNA. These effects were blunted in S1P2-/- cells, and S1P2-/- hMF exhibited reduced mitogenic and comitogenic responses to S1P. These results unravel a novel major role of S1P2 in the wound healing response to acute liver injury by a mechanism involving enhanced proliferation of hMF.

Topics: Acute Disease; Animals; Becaplermin; Carbon Tetrachloride Poisoning; Cell Division; Cells, Cultured; Chemical and Drug Induced Liver Injury; DNA Replication; Enzyme Induction; Extracellular Matrix; Fibroblasts; Gene Expression Regulation; Liver Regeneration; Lysophospholipids; Mice; Mice, Inbred C57BL; Mice, Knockout; Myoblasts, Smooth Muscle; Necrosis; Phosphotransferases (Alcohol Group Acceptor); Platelet-Derived Growth Factor; Proliferating Cell Nuclear Antigen; Proto-Oncogene Proteins c-sis; Receptors, Lysosphingolipid; Sphingosine; Sphingosine-1-Phosphate Receptors; Tissue Inhibitor of Metalloproteinase-1; Transforming Growth Factor beta1

Fumonisins are causative agents of diseases in mice and rats, including liver and renal toxicities, as well as cancer, and are specific inhibitors of ceramide synthase in the metabolism of sphingolipid. The purpose of this study was to determine whether an elevated level of sphingoid base 1-phosphate was related to the expressions of metabolism enzymes in the liver of fumonisin B1 (FB1)-treated mice and acted as a contributing factor to hepatotoxicity. In our previous study, FB1 was confirmed to be toxic to both liver and kidneys, coupled with simultaneous elevation of sphinganine 1-phosphate. ICR mice were treated intraperitoneally with 10 mg/kg/day FB1 for 5 days, with the concentrations of sphingolipid metabolites in the serum and liver measured using HPLC following Bligh-Dyer extraction. The levels of sphingoid bases and their 1-phosphates in the serum and liver were markedly elevated in response to treatment with FB1. In the liver, FB1 increased the expression of sphingosine kinase and inhibited the expression of sphingosine 1-phosphate lyase. The cleaved form of caspase-3 was detected in the liver of FB1-treated mice, indicating the occurrence of apoptosis in the liver following exposure to FB1. The expressions of proapoptotic signaling molecules, such as phosphorylated forms of c-Jun N-terminus kinase (JNK), p38 MAPK and extracellular signal-regulated kinase (ERK), were increased in the liver of FB1-treated mice. In conclusion, these results suggest the elevation of sphingoid base 1-phosphate, as a result of the activation of sphingosine kinase and the inhibition of sphingosine 1-phosphate lyase, may be a major target for FB1-induced hepatotoxicity via the activation of an apoptotic signaling pathway.

Topics: Aldehyde-Lyases; Animals; Caspase 3; Chemical and Drug Induced Liver Injury; Fumonisins; Liver; Lysophospholipids; Mice; Mice, Inbred ICR; Mitogen-Activated Protein Kinases; Mycotoxins; Phosphotransferases (Alcohol Group Acceptor); Sphingosine