title: Aggregated LDL in contact with macrophages induces local increases in free cholesterol levels that regulate local actin polymerization.
abstract: OBJECTIVE
  Interaction of macrophages with aggregated matrix-anchored lipoprotein deposits is an important initial step in atherogenesis. Aggregated lipoproteins require different cellular uptake processes than those used for endocytosis of monomeric lipoproteins. In this study, we tested the hypothesis that engagement of aggregated LDL (agLDL) by macrophages could lead to local increases in free cholesterol levels and that these increases in free cholesterol regulate signals that control cellular actin.
  
  
  RESULTS
  AgLDL resides for prolonged periods in surface-connected compartments. Although agLDL is still extracellular, we demonstrate that an increase in free cholesterol occurs at sites of contact between agLDL and cells because of hydrolysis of agLDL-derived cholesteryl ester. This increase in free cholesterol causes enhanced actin polymerization around the agLDL. Inhibition of cholesteryl ester hydrolysis results in decreased actin polymerization.
  
  
  CONCLUSIONS
  We describe a novel process that occurs during agLDL-macrophage interactions in which local release of free cholesterol causes local actin polymerization, promoting a pathological positive feedback loop for increased catabolism of agLDL and eventual foam cell formation.
authors: Department of Biochemistry, Weill Cornell Medical College, New York, NY 10065, USA.
authors: Inna
authors: I
authors: Grosheva
authors: Abigail S
authors: AS
authors: Haka
authors: Chunbo
authors: C
authors: Qin
authors: Lynda M
authors: LM
authors: Pierini
authors: Frederick R
authors: FR
authors: Maxfield
mesh_terms: D000199:Actins / Q000737:chemistry*; D002784:Cholesterol / Q000378:metabolism*; D002788:Cholesterol Esters / Q000378:metabolism; D005372:Filipin / Q000032:analysis; D006801:Humans; D008077:Lipoproteins, LDL / Q000502:physiology*; D018942:Macrolides / Q000494:pharmacology; D008264:Macrophages / Q000502:physiology*; D011108:Polymers / Q000737:chemistry; D002787:Sterol Esterase / Q000502:physiology; D020764:cdc42 GTP-Binding Protein / Q000502:physiology; D020744:rac GTP-Binding Proteins / Q000502:physiology
chemical_list: D000199:Actins; D002788:Cholesterol Esters; D008077:Lipoproteins, LDL; D018942:Macrolides; D011108:Polymers; D005372:Filipin; C040929:bafilomycin A1; D002784:Cholesterol; D002787:Sterol Esterase; D020764:cdc42 GTP-Binding Protein; D020744:rac GTP-Binding Proteins