title: Urokinase-type plasminogen activator (uPA) decreases hepatic SR-BI expression and impairs HDL-mediated reverse cholesterol transport.
abstract: OBJECTIVE
  The aim of the present study was to investigate the effect of urokinase-type plasminogen activator (uPA) on the expression of the scavenger receptor class B type I (SR-BI) in hepatocytes, and its impact on the removal of HDL-cholesteryl ester (CE) in the liver.
  
  
  RESULTS
  Huh7 hepatoma cell lines were incubated with increasing concentrations of uPA. uPA dose-dependently decreased SR-BI protein expression, as determined by flow cytometry (FACS) and by Western blot assays, and down-regulated SR-BI gene expression. Functionally, uPA decreased both the cellular binding of HDL to Huh7 hepatocytes, and the selective uptake of CE from HDL, as determined by several methods including BODIPY staining, cellular cholesterol determination and chasing radio-labeled CE transfer from HDL to the cells. These results were further confirmed using primary rat hepatocytes. The effect of uPA on hepatic SR-BI expression was mediated via binding to the uPA receptor (uPAR). In vivo, SR-BI protein and gene expressions were found to be increased in hepatocytes derived from the uPAR-KO mice compared to C57Bl/6 mice, and in parallel HDL-cholesterol levels in plasma derived from uPAR-KO mice were decreased. Moreover, deficiency of uPAR significantly accelerated the plasma decay of injected HDL-[(3)H]CE.
  
  
  CONCLUSIONS
  The results of this study suggest that uPA decreases the removal of HDL-CE in the liver via suppression of the hepatic SR-BI expression. Impaired reverse cholesterol transport (RCT) may result in atherogenic dysfunctional HDL metabolism and may contribute to atherosclerosis development.
authors: The Lipid Research Laboratory, Technion Faculty of Medicine, The Rappaport Family Institute for Research in the Medical Sciences, and Rambam Medical Center, Haifa 31096, Israel.
authors: Semyon
authors: S
authors: Chulsky
authors: The Lipid Research Laboratory, Technion Faculty of Medicine, The Rappaport Family Institute for Research in the Medical Sciences, and Rambam Medical Center, Haifa 31096, Israel.
authors: Nicole
authors: N
authors: Paland
authors: The Lipid Research Laboratory, Technion Faculty of Medicine, The Rappaport Family Institute for Research in the Medical Sciences, and Rambam Medical Center, Haifa 31096, Israel.
authors: Aviva
authors: A
authors: Lazarovich
authors: The Lipid Research Laboratory, Technion Faculty of Medicine, The Rappaport Family Institute for Research in the Medical Sciences, and Rambam Medical Center, Haifa 31096, Israel. Electronic address: Fuhrman@tx.technion.ac.il.
authors: Bianca
authors: B
authors: Fuhrman
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D002784:Cholesterol / Q000378:metabolism; D002788:Cholesterol Esters / Q000378:metabolism*; D022781:Hepatocytes / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D008075:Lipoproteins, HDL / Q000378:metabolism*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D051381:Rats; D055293:Receptors, Urokinase Plasminogen Activator / Q000378:metabolism; D051122:Scavenger Receptors, Class B / Q000096:biosynthesis*; D014568:Urokinase-Type Plasminogen Activator / Q000494:pharmacology*
chemical_list: D002788:Cholesterol Esters; C059714:HDL cholesteryl ester; D008075:Lipoproteins, HDL; D055293:Receptors, Urokinase Plasminogen Activator; D051122:Scavenger Receptors, Class B; D002784:Cholesterol; D014568:Urokinase-Type Plasminogen Activator
keywords: HDL; Reverse cholesterol transport; SR-BI; Urokinase