title: Regulation of plasma ceramide levels with fatty acid oversupply: evidence that the liver detects and secretes de novo synthesised ceramide.
abstract: OBJECTIVE
  Plasma ceramide concentrations correlate with insulin sensitivity, inflammation and atherosclerotic risk. We hypothesised that plasma ceramide concentrations are increased in the presence of elevated fatty acid levels and are regulated by increased liver serine C-palmitoyltransferase (SPT) activity.
  
  
  METHODS
  Lean humans and rats underwent an acute lipid infusion and plasma ceramide levels were determined. One group of lipid-infused rats was administered myriocin to inhibit SPT activity. Liver SPT activity was determined in lipid-infused rats, and obese, insulin resistant mice. The time and palmitate dose-dependent synthesis of intracellular and secreted ceramide was determined in HepG2 liver cells.
  
  
  RESULTS
  Plasma ceramide levels were increased during lipid infusion in humans and rats, and in obese, insulin-resistant mice. The increase in plasma ceramide was not associated with changes in liver SPT activity, and inhibiting SPT activity by ~50% did not alter plasma ceramide levels in lipid-infused rats. In HepG2 liver cells, palmitate incorporation into extracellular ceramide was both dose- and time-dependent, suggesting the liver cells rapidly secreted the newly synthesised ceramide.
  
  
  CONCLUSIONS
  Elevated systemic fatty acid availability increased plasma ceramide but this was not associated with changes in hepatic SPT activity, suggesting that liver ceramide synthesis is driven by substrate availability rather than increased SPT activity. This report also provides evidence that the liver is sensitive to the intracellular ceramide concentration, and an increase in liver ceramide secretion may help protect the liver from the deleterious effects of intracellular ceramide accumulation.
authors.affiliation: Department of Physiology, Monash University, Building 13F, Clayton, VIC, 3800, Australia. matthew.watt@monash.edu.
authors.forename: M J
authors.initials: MJ
authors.lastname: Watt
authors.affiliation: Department of Physiology, Monash University, Building 13F, Clayton, VIC, 3800, Australia.
authors.forename: A C
authors.initials: AC
authors.lastname: Barnett
authors.affiliation: Department of Physiology, Monash University, Building 13F, Clayton, VIC, 3800, Australia.|Baker IDI Heart & Diabetes Institute, Melbourne, VIC, Australia.
authors.forename: C R
authors.initials: CR
authors.lastname: Bruce
authors.affiliation: School of Kinesiology, University of Michigan, Ann Arbor, MI, USA.|Department of Orthopaedic Surgery, University of California, San Diego, CA, USA.
authors.forename: S
authors.initials: S
authors.lastname: Schenk
authors.affiliation: School of Kinesiology, University of Michigan, Ann Arbor, MI, USA.
authors.forename: J F
authors.initials: JF
authors.lastname: Horowitz
authors.affiliation: Department of Physiology, Monash University, Building 13F, Clayton, VIC, 3800, Australia. andrew.hoy@sydney.edu.au.|Discipline of Physiology, University of Sydney, Anderson Stuart Building (F13), Sydney, NSW, 2006, Australia. andrew.hoy@sydney.edu.au.
authors.forename: A J
authors.initials: AJ
authors.lastname: Hoy
mesh_terms: D000328:Adult; D000818:Animals; D002518:Ceramides / Q000097:blood* / Q000378:metabolism; D004195:Disease Models, Animal; D005227:Fatty Acids / Q000494:pharmacology*; D005260:Female; D056945:Hep G2 Cells / Q000378:metabolism; D006801:Humans; D007333:Insulin Resistance / Q000502:physiology; D008099:Liver / Q000378:metabolism*; D008297:Male; D051379:Mice; D008820:Mice, Obese; D023421:Models, Animal; D009765:Obesity / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D051102:Serine C-Palmitoyltransferase / Q000378:metabolism*
chemical_list: D002518:Ceramides; D005227:Fatty Acids; D051102:Serine C-Palmitoyltransferase