title: New evidence for the role of ceramide in the development of hepatic insulin resistance.
abstract: OBJECTIVE
  There are few and contradictory data on the role of excessive accumulation of intracellular sphingolipids, particularly ceramides, in the development of hepatic insulin resistance. In our study we assessed accumulated sphingolipid fractions and clarify the mechanisms of hepatic insulin resistance development as well as involvement of fatty acid and ceramide transporters in this process.
  
  
  METHODS
  In culture of primary rat hepatocytes, exposed to high concentration of palmitic acid (0.75 mM) during short and prolonged incubation, high performance liquid chromatography was used to assess intra- and extracellular sphingolipid fractions content. Degree of palmitate-induced insulin resistance was estimated by measuring changes in phosphorylation of insulin pathway proteins by western blotting as well as changes in expression of different type of transporters.
  
  
  RESULTS
  In our study short and prolonged exposure of primary hepatocytes to palmitic acid resulted in increased intracellular accumulation of ceramide which inhibited insulin signaling pathway. We observed a significant increase in the expression of fatty-acid transport protein (FATP2) and ceramide transfer protein (CERT) what is consistent with enhanced intracellular ceramide content. The content of extracellular ceramide was increased nearly threefold after short and twofold after long incubation period. Expression of microsomal triglyceride transfer protein (MTP) and ATP-binding cassette transporter (ABCA1) was increased significantly mainly after short palmitate incubation.
  
  
  CONCLUSIONS
  Our data showed that increase in intarcellular ceramide content contributes to the development of hepatic insulin resistance. We suggest pivotal role of transporters in facilitating fatty acid influx (FATP2), accumulation of ceramides (CERT) and export to the media (MTP and ABCA1).
authors: Department of Physiology, Medical University of Bialystok, Białystok, Poland.
authors: Karolina
authors: K
authors: Konstantynowicz-Nowicka
authors: Department of Physiology, Medical University of Bialystok, Białystok, Poland.
authors: Ewa
authors: E
authors: Harasim
authors: Department of Physiology, Medical University of Bialystok, Białystok, Poland.
authors: Marcin
authors: M
authors: Baranowski
authors: Department of Physiology, Medical University of Bialystok, Białystok, Poland.
authors: Adrian
authors: A
authors: Chabowski
mesh_terms: D000818:Animals; D001692:Biological Transport; D053898:Biosynthetic Pathways; D002478:Cells, Cultured; D002518:Ceramides / Q000502:physiology*; D015870:Gene Expression; D022781:Hepatocytes / Q000378:metabolism; D007333:Insulin Resistance; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism; D008297:Male; D061251:Primary Cell Culture; D017208:Rats, Wistar; D051102:Serine C-Palmitoyltransferase / Q000378:metabolism
chemical_list: D002518:Ceramides; D047908:Intracellular Signaling Peptides and Proteins; D051102:Serine C-Palmitoyltransferase
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