title: Fatty acid-induced nuclear translocation of heparanase uncouples glucose metabolism in endothelial cells.
abstract: OBJECTIVE
  Heparanase is an endoglycosidase that specifically cleaves carbohydrate chains of heparan sulfate. We have recently reported that high fatty acid increased the nuclear content of endothelial heparanase. Here, we examined the mechanism and the consequences behind this nuclear translocation of heparanase.
  
  
  RESULTS
  Bovine coronary artery endothelial cells were grown to confluence and incubated with palmitic acid. Palmitic acid induced rapid nuclear accumulation of heparanase that was dependent on Bax activation and lysosome permeabilization. Heat shock protein 90 was an important mediator of palmitic acid-induced shuttling of heparanase to the nucleus. Nuclear heparanase promoted cleavage of heparan sulfate, a potent inhibitor of histone acetyltransferase activity and gene transcription. A TaqMan gene expression assay revealed an increase in genes related to glucose metabolism and inflammation. In addition, glycolysis was uncoupled from glucose oxidation, resulting in accumulation of lactate.
  
  
  CONCLUSIONS
  The results presented in this study demonstrate that fatty acid can provoke lysosomal release of heparanase, its nuclear translocation, activation of genes controlling glucose metabolism, and accumulation of lactate. Given that lactate and inflammation have been implicated in the progression of atherosclerosis, our data may serve to reduce the associated cardiovascular complications seen during diabetes.
authors: Molecular and Cellular Pharmacology Group, Faculty of Pharmaceutical Sciences, The University of British Columbia, 2146 East Mall, Vancouver, B.C., Canada V6T 1Z3.
authors: Fang
authors: F
authors: Wang
authors: Ying
authors: Y
authors: Wang
authors: Dahai
authors: D
authors: Zhang
authors: Prasanth
authors: P
authors: Puthanveetil
authors: James D
authors: JD
authors: Johnson
authors: Brian
authors: B
authors: Rodrigues
mesh_terms: D000818:Animals; D001167:Arteritis / Q000378:metabolism; D002417:Cattle; D002467:Cell Nucleus / Q000378:metabolism*; D002478:Cells, Cultured; D003331:Coronary Vessels / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D004730:Endothelium, Vascular / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism*; D005227:Fatty Acids / Q000494:pharmacology*; D005947:Glucose / Q000378:metabolism*; D005966:Glucuronidase / Q000378:metabolism*; D018841:HSP90 Heat-Shock Proteins / Q000378:metabolism; D006497:Heparan Sulfate / Q000378:metabolism; D007773:Lactates / Q000378:metabolism; D008247:Lysosomes / Q000187:drug effects / Q000378:metabolism; D023421:Models, Animal; D019308:Palmitic Acid / Q000494:pharmacology; D000099175:Heparanase
chemical_list: D005227:Fatty Acids; D005947:Glucose; D005966:Glucuronidase; D018841:HSP90 Heat-Shock Proteins; D006497:Heparan Sulfate; D007773:Lactates; D019308:Palmitic Acid; D000099175:Heparanase