title: Effect of fatty acid chain length and thioesterification on the augmentation of expression of plasminogen activator inhibitor-1.
abstract: OBJECTIVE
  Concentrations in blood of plasminogen activator inhibitor type 1 (PAI-1) and circulating free (non-esterified) fatty acids (FFA) are increased in diabetes and may accelerate atherosclerosis. We have shown that FFA increase expression of PAI-1 by activation of a transcription factor that binds to the repeated sequence 5'-TG(G/C) 1-2CTG-3'. This study was designed to determine whether FFA chain length, saturation, or both affect agonist properties and whether agonist properties are mediated by activated, thioesterified FFA (fatty acyl-CoA).
  
  
  RESULTS
  Human hepatoma cells were exposed to selected FFA associated with bovine serum albumin (BSA). Triacsin C (5 microM) was used to inhibit production of fatty acyl-CoA. PAI-1 was assayed by enzyme linked immunosorbent assay. Maximal induction of PAI-1 was similar with medium and long chain FFA (fold induction of PAI-1 accumulated in conditioned media compared with control: C10 = 1.8 +/- 0.1, C12 = 2.0 +/- 0.1, C14 = 2.0 +/- 0.2, C16 = 1.4 +/- 0.1, C18 = 1.6 +/- 0.1, C20 = 1.32 +/- 0.1, p < 0.005 for each compared with control). Increased unsaturation did not alter the agonist properties of FFA (fold induction with C16: 0 = 1.4 +/- 0.1, C16: 1 = 1.4 +/- 0.1; C18: 0 = 1.6 +/- 0.1, C18: 1 = 1.5 +/- 0.1, C18: 2 = 1.6 +/- 0.1, C18: 3 = 1.4 +/- 0.1 and C20: 4 = 1.3 +/- 0.1, C20: 5 = 1.4 +/- 0.1, n = 6). However, maximal effects were seen with lower concentrations of longer chain FFA. Triacsin C consistently attenuated effects of FFA.
  
  
  CONCLUSIONS
  Longer chain FFA exhibit maximal effects at lower concentrations. Augmented expression of PAI-1 is mediated by the fatty acyl-CoA derivative. These criteria identify targets for therapy designed to normalize expression of PAI-1 and retard progression of atherosclerosis in subjects with elevated concentrations of FFA in blood including those with insulin resistance.
authors.affiliation: Department of Medicine, University of Vermont, 208A South Park Drive, Suite 2, Colchester, VT 05446, USA.
authors.forename: Y
authors.initials: Y
authors.lastname: Chen
authors.forename: B E
authors.initials: BE
authors.lastname: Sobel
authors.forename: D J
authors.initials: DJ
authors.lastname: Schneider
mesh_terms: D000214:Acyl Coenzyme A / Q000187:drug effects / Q000378:metabolism*; D000704:Analysis of Variance; D000818:Animals; D006528:Carcinoma, Hepatocellular / Q000235:genetics* / Q000473:pathology; D002417:Cattle; D004347:Drug Interactions; D005230:Fatty Acids, Nonesterified / Q000494:pharmacology*; D005786:Gene Expression Regulation; D022781:Hepatocytes / Q000187:drug effects; D006801:Humans; D008113:Liver Neoplasms / Q000235:genetics* / Q000473:pathology; D010170:Palmitoyl-CoA Hydrolase / Q000494:pharmacology*; D017395:Plasminogen Activator Inhibitor 1 / Q000235:genetics*; D011336:Probability; D012680:Sensitivity and Specificity; D014407:Tumor Cells, Cultured / Q000187:drug effects; D015854:Up-Regulation
chemical_list: D000214:Acyl Coenzyme A; D005230:Fatty Acids, Nonesterified; D017395:Plasminogen Activator Inhibitor 1; D010170:Palmitoyl-CoA Hydrolase