title: Involvement of Sphingosine 1-Phosphate in Palmitate-Induced Non-Alcoholic Fatty Liver Disease.
abstract: OBJECTIVE
  Ectopic lipid accumulation in hepatocytes has been identified as a risk factor for the progression of liver fibrosis and is strongly associated with obesity. In particular, the saturated fatty acid palmitate is involved in initiation of liver fibrosis via formation of secondary metabolites by hepatocytes that in turn activate hepatic stellate cells (HSCs) in a paracrine manner.
  
  
  METHODS
  α-smooth muscle actin-expression (α-SMA) as a marker of liver fibrosis was investigated via western blot analysis and immunofluorescence microscopy in HSCs (LX-2). Sphingolipid metabolism and the generation of the bioactive secondary metabolite sphingosine 1-phosphate (S1P) in response to palmitate were analyzed by LC-MS/MS in hepatocytes (HepG2). To identify the molecular mechanism involved in the progression of liver fibrosis real-time PCR analysis and pharmacological modulation of S1P receptors were performed.
  
  
  RESULTS
  Palmitate oversupply increased intra- and extracellular S1P-concentrations in hepatocytes. Conditioned medium from HepG2 cells initiated fibrosis by enhancing α-SMA-expression in LX-2 in a S1P-dependent manner. In accordance, fibrotic response in the presence of S1P was also observed in HSCs. Pharmacological inhibition of S1P receptors demonstrated that S1P3 is the crucial receptor subtype involved in this process.
  
  
  CONCLUSIONS
  S1P is synthesized in hepatocytes in response to palmitate and released into the extracellular environment leading to an activation of HSCs via the S1P3 receptor.
authors.affiliation: Faculty of Mathematics and Natural Science, Institute of Nutritional Science, Department of Toxicology, University of Potsdam, Potsdam, Germany.
authors.forename: Frdoos
authors.initials: F
authors.lastname: Al Fadel
authors.forename: Susann
authors.initials: S
authors.lastname: Fayyaz
authors.forename: Lukasz
authors.initials: L
authors.lastname: Japtok
authors.forename: Burkhard
authors.initials: B
authors.lastname: Kleuser
mesh_terms: D000199:Actins / Q000378:metabolism; D017077:Culture Media, Conditioned / Q000494:pharmacology; D056945:Hep G2 Cells; D055166:Hepatic Stellate Cells / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D022781:Hepatocytes / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D006801:Humans; D008103:Liver Cirrhosis / Q000378:metabolism / Q000473:pathology; D008246:Lysophospholipids / Q000494:pharmacology*; D065626:Non-alcoholic Fatty Liver Disease / Q000139:chemically induced* / Q000378:metabolism*; D010168:Palmitates / Q000009:adverse effects*; D049349:Receptors, Lysosphingolipid / Q000378:metabolism; D013110:Sphingosine / Q000031:analogs & derivatives* / Q000494:pharmacology
chemical_list: C541116:ACTA2 protein, human; D000199:Actins; D017077:Culture Media, Conditioned; D008246:Lysophospholipids; D010168:Palmitates; D049349:Receptors, Lysosphingolipid; C060506:sphingosine 1-phosphate; D013110:Sphingosine