@article{AlFadelFayyazJaptoketal.2016,
  author    = {Al Fadel, Frdoos and Fayyaz, Susann and Japtok, Lukasz and Kleuser, Burkhard},
  title     = {Involvement of Sphingosine 1-Phosphate in Palmitate-Induced Non-Alcoholic Fatty Liver Disease},
  series = {Cellular physiology and biochemistry : international journal of experimental cellular physiology, biochemistry and pharmacology},
  volume    = {40},
  journal   = {Cellular physiology and biochemistry : international journal of experimental cellular physiology, biochemistry and pharmacology},
  publisher = {Karger},
  address   = {Basel},
  issn      = {1015-8987},
  doi       = {10.1159/000453213},
  pages     = {1637 -- 1645},
  year      = {2016},
  abstract  = {Background/Aims: 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: a-smooth muscle actin-expression (alpha-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 I-phosphate (SIP) 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 SIP receptors were performed. Results: Palmitate oversupply increased intra- and extracellular SIP-concentrations in hepatocytes. Conditioned medium from HepG2 cells initiated fibrosis by enhancing alpha-SMA-expression in LX-2 in a S1P-dependent manner In accordance, fibrotic response in the presence of SIP was also observed in HSCs. Pharmacological inhibition of SIP receptors demonstrated that S1P(3) is the crucial receptor subtype involved in this process. Conclusion: SIP is synthesized in hepatocytes in response to palmitate and released into the extracellular environment leading to an activation of HSCs via the S1P(3) receptor (C) 2016 The Author(s) Published by S. Karger AG, Basel},
  language  = {en}
}
@misc{FayyazJaptokKleuser2014,
  author    = {Fayyaz, Susann and Japtok, Lukasz and Kleuser, Burkhard},
  title     = {Divergent role of sphingosine 1-Phosphate on insulin resistance},
  series = {Cellular physiology and biochemistry : international journal of experimental cellular physiology, biochemistry and pharmacology},
  volume    = {34},
  journal   = {Cellular physiology and biochemistry : international journal of experimental cellular physiology, biochemistry and pharmacology},
  number    = {1},
  publisher = {Karger},
  address   = {Basel},
  issn      = {1015-8987},
  doi       = {10.1159/000362990},
  pages     = {134 -- 147},
  year      = {2014},
  abstract  = {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.},
  language  = {en}
}