title: Involvement of sphingosine 1-phosphate in palmitate-induced insulin resistance of hepatocytes via the S1P2 receptor subtype.
abstract: OBJECTIVE
  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.
  
  
  METHODS
  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.
  
  
  RESULTS
  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 S1P2 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 S1P2, was not able to inhibit insulin signalling.
  
  
  CONCLUSIONS
  These data indicate that palmitate is metabolised by hepatocytes to S1P, which acts via stimulation of the S1P2 receptor to impair insulin signalling. In particular, S1P2 inhibition could be considered as a novel therapeutic target for the treatment of insulin resistance.
authors.affiliation: Faculty of Mathematics and Natural Science, Institute of Nutritional Science, Department of Toxicology, University of Potsdam, Arthur-Scheunert Allee 114-116, 14558, Nuthetal, Potsdam, Germany.
authors.forename: Susann
authors.initials: S
authors.lastname: Fayyaz
authors.forename: Janin
authors.initials: J
authors.lastname: Henkel
authors.forename: Lukasz
authors.initials: L
authors.lastname: Japtok
authors.forename: Stephanie
authors.initials: S
authors.lastname: Krämer
authors.forename: Georg
authors.initials: G
authors.lastname: Damm
authors.forename: Daniel
authors.initials: D
authors.lastname: Seehofer
authors.forename: Gerhard P
authors.initials: GP
authors.lastname: Püschel
authors.forename: Burkhard
authors.initials: B
authors.lastname: Kleuser
mesh_terms: D000818:Animals; D015153:Blotting, Western; D002853:Chromatography, Liquid; D003924:Diabetes Mellitus, Type 2 / Q000378:metabolism*; D022781:Hepatocytes / Q000187:drug effects / Q000502:physiology*; D007166:Immunosuppressive Agents / Q000378:metabolism / Q000494:pharmacology*; D007328:Insulin / Q000378:metabolism; D007333:Insulin Resistance; D008246:Lysophospholipids / Q000378:metabolism*; D008297:Male; D051379:Mice; D008820:Mice, Obese; D010755:Organophosphates / Q000378:metabolism / Q000494:pharmacology*; D010168:Palmitates / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D013110:Sphingosine / Q000031:analogs & derivatives* / Q000378:metabolism / Q000494:pharmacology
chemical_list: C525008:FTY 720P; D007166:Immunosuppressive Agents; D007328:Insulin; D008246:Lysophospholipids; D010755:Organophosphates; D010168:Palmitates; C060506:sphingosine 1-phosphate; D013110:Sphingosine