title: Urokinase-type plasminogen activator (uPA) stimulates triglyceride synthesis in Huh7 hepatoma cells via p38-dependent upregulation of DGAT2.
abstract: OBJECTIVE
  The liver is the central organ of fatty acid and triglyceride metabolism. Oxidation and synthesis of fatty acids and triglycerides is under the control of peroxisome-proliferator-activated receptors (PPAR) α. Impairment of these receptors' function contributes to the accumulation of triglycerides in the liver resulting in non-alcoholic fatty liver disease. Urokinase-type plasminogen activator (uPA) was shown to regulate gene expression in the liver involving PPARγ transcriptional activity. In this study we questioned whether uPA modulates triglyceride metabolism in the liver, and investigated the mechanisms involved in the observed processes.
  
  
  RESULTS
  Huh7 hepatoma cells were incubated with increasing concentrations of uPA for 24 h uPA dose-dependently increased the cellular triglyceride mass, and this effect resulted from increased de novo triglyceride synthesis mediated by the enzyme diglyceride acyltransferase 2 (DGAT2). Also, the amount of free fatty acids was highly up regulated by uPA through activation of the transcription factor SREBP-1. Chemical activation of PPARα further increased uPA-stimulated triglyceride synthesis, whereas inhibition of p38, an upstream activator of PPARα, completely abolished the stimulatory effect of uPA on both triglyceride synthesis and DGAT2 upregulation. The effect of uPA on triglyceride synthesis in Huh7 cells was mediated via binding to its receptor, the uPAR. In vivo studies in uPAR(-/-) mice demonstrated that no lipid droplets were observed in their livers compared to C57BL/6 mice and the triglyceride levels were significantly lower.
  
  
  CONCLUSIONS
  This study presents a new biological function of the uPA/uPAR system in the metabolism of triglycerides and might present a new target for an early therapeutic intervention for NAFLD.
authors.affiliation: The Lipid Research Laboratory, Rappaport Faculty of Medicine, Technion-Israel Institute of Technology, Haifa, Israel.
authors.forename: Nicole
authors.initials: N
authors.lastname: Paland
authors.affiliation: The Lipid Research Laboratory, Rambam Health Care Campus, Haifa, Israel.
authors.forename: Aviva
authors.initials: A
authors.lastname: Gamliel-Lazarovich
authors.affiliation: Department of Anatomy and Cell Biology, Rappaport Faculty of Medicine, Technion-Israel Institute of Technology, Haifa, Israel.
authors.forename: Raymond
authors.initials: R
authors.lastname: Coleman
authors.affiliation: The Lipid Research Laboratory, Technion Faculty of Medicine and Rambam Health Care Campus, Haifa 31096, Israel. Electronic address: fuhrman@tx.technion.ac.il.
authors.forename: Bianca
authors.initials: B
authors.lastname: Fuhrman
mesh_terms: D000818:Animals; D006528:Carcinoma, Hepatocellular / Q000378:metabolism*; D045744:Cell Line, Tumor; D051048:Diacylglycerol O-Acyltransferase / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D005227:Fatty Acids / Q000737:chemistry; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008055:Lipids / Q000737:chemistry; D008099:Liver / Q000378:metabolism; D008113:Liver Neoplasms / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D051780:Sterol Regulatory Element Binding Protein 1 / Q000378:metabolism; D014280:Triglycerides / Q000378:metabolism*; D015854:Up-Regulation; D014568:Urokinase-Type Plasminogen Activator / Q000378:metabolism*; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism*
chemical_list: D005227:Fatty Acids; D008055:Lipids; C497387:SREBF1 protein, human; C497388:Srebf1 protein, mouse; D051780:Sterol Regulatory Element Binding Protein 1; D014280:Triglycerides; C494885:DGAT2 protein, human; C516957:DGAT2 protein, mouse; D051048:Diacylglycerol O-Acyltransferase; D048051:p38 Mitogen-Activated Protein Kinases; D014568:Urokinase-Type Plasminogen Activator
keywords: DGAT2; Fatty acids; PPARα; Triglycerides; Urokinase; p38