title: VLDL-induced triglyceride accumulation in human macrophages is mediated by modulation of LPL lipolytic activity in the absence of change in LPL mass.
abstract: Mixed dyslipidemia of phenotype IIB is characterized by elevated levels of very low density lipoprotein (VLDL)-1 and VLDL-2 subfractions and of low density lipoprotein (LDL), which are associated with premature formation of atherosclerotic plaques, characterized by the presence of lipid-rich macrophage foam cells. Lipoprotein lipase (LPL) is a key factor in mediating macrophage lipid accumulation and foam-cell formation from native VLDL particles. The action of macrophage-derived LPL in the induction of intracellular lipid accumulation from triglyceride-rich lipoprotein (TRL) subfractions (VLDL-1, VLDL-2) is, however, indeterminate, as is the potential role of VLDL-1 and VLDL-2 in modulating macrophage LPL expression. We evaluated the role of LPL in the interaction of type IIB VLDL-1 and VLDL-2 with human macrophages. Both VLDL-1 and VLDL-2 subfractions induced significant accumulation of triglyceride (9.8-fold, P<0.0001, and 4.8-fold, P<0.0001, respectively) and of free cholesterol content (1.4-fold, P<0.001, and 1.2-fold, P=0.02, respectively). Specific inhibition (90%) of the lipolytic activity of endogenous LPL by tetrahydrolipstatin (THL) in the presence of VLDL-1 or VLDL-2 resulted in marked reduction in cellular loading of both triglycerides (-89%, P=0.008, and -89%, P=0.015, respectively) and free cholesterol (-76%, P=0.02, and -55%, P=0.06 respectively). Furthermore, VLDL-1 and VLDL-2 induced marked increase in macrophage-derived LPL enzyme activity (+81%, P=0.002, and +45%, P=0.02), but did not modulate macrophage-derived LPL mRNA and protein expression; consequently, LPL specific activity was significantly increased from 1.6 mU/microg at baseline to 4.1 mU/microg (P=0.01) and 3.1 mU/microg (P=0.05), in the presence of VLDL-1 and VLDL-2, respectively. We conclude that type IIB VLDL-1 and VLDL-2 induce triglyceride accumulation in human monocyte-macrophages primarily via the lipolytic action of LPL, which may involve stabilization and activation of the macrophage-secreted enzyme, rather than via modulation of enzyme production.
authors.affiliation: National Institute for Health and Medical Research (INSERM) Unite 551, Hôpital de la Pitié, 83, Boulevard de l'Hôpital, F-75651 Paris Cedex 13, France.
authors.forename: Dragana
authors.initials: D
authors.lastname: Milosavljevic
authors.forename: Anatol
authors.initials: A
authors.lastname: Kontush
authors.forename: Sabine
authors.initials: S
authors.lastname: Griglio
authors.forename: Gilles
authors.initials: G
authors.lastname: Le Naour
authors.forename: Joëlle
authors.initials: J
authors.lastname: Thillet
authors.forename: M John
authors.initials: MJ
authors.lastname: Chapman
mesh_terms: D002478:Cells, Cultured; D002784:Cholesterol / Q000032:analysis / Q000378:metabolism / Q000494:pharmacology; D004789:Enzyme Activation; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005487:Foam Cells / Q000378:metabolism; D006801:Humans; D006938:Hyperlipoproteinemia Type II / Q000097:blood*; D007783:Lactones / Q000494:pharmacology; D008066:Lipolysis; D008071:Lipoprotein Lipase / Q000032:analysis / Q000037:antagonists & inhibitors / Q000378:metabolism*; D008074:Lipoproteins / Q000494:pharmacology; D008079:Lipoproteins, VLDL / Q000097:blood* / Q000737:chemistry / Q000302:isolation & purification; D008264:Macrophages / Q000378:metabolism*; D000077403:Orlistat; D012333:RNA, Messenger / Q000032:analysis; D014280:Triglycerides / Q000032:analysis / Q000378:metabolism
chemical_list: D004791:Enzyme Inhibitors; D007783:Lactones; D008074:Lipoproteins; D008079:Lipoproteins, VLDL; D012333:RNA, Messenger; D014280:Triglycerides; C030104:lipoprotein cholesterol; D000077403:Orlistat; D002784:Cholesterol; D008071:Lipoprotein Lipase