title: Dual roles for lipolysis and oxidation in peroxisome proliferation-activator receptor responses to electronegative low density lipoprotein.
abstract: Low density lipoprotein (LDL) exists in various forms that possess unique characteristics, including particle content and metabolism. One circulating subfraction, electronegative LDL (LDL(-)), which is increased in familial hypercholesterolemia and diabetes, is implicated in accelerated atherosclerosis. Cellular responses to LDL(-) remain poorly described. Here we demonstrate that LDL(-) increases tumor necrosis factor alpha (TNFalpha)-induced inflammatory responses through NF kappa B and AP-1 activation with corresponding increases in vascular cell adhesion molecule-1 (VCAM1) expression. LDL receptor overexpression increased these effects. In contrast, exposing LDL(-) to the key lipolytic enzyme lipoprotein lipase (LPL) reversed these responses, inhibiting VCAM1 below levels seen with TNFalpha alone. LPL is known to act on lipoproteins to generate endogenous peroxisomal proliferator-activated receptor alpha (PPAR alpha) ligand, thus limiting inflammation. These responses varied according to the lipoprotein substrate triglyceride content (very low density lipoprotein >> LDL > high density lipoprotein). The PPAR alpha activation seen with LDL, however, was disproportionately high. We show here that MUT LDL activates PPAR alpha to an extent proportional to its LDL(-) content. As compared with LDL(-) alone, LPL-treated LDL(-) increased PPAR alpha activation 20-fold in either cell-based transfection or radioligand displacement assays. LPL-treated LDL(-) suppressed NF kappa B and AP-1 activation, increasing expression of the PPAR alpha target gene I kappa B alpha, although only in the genetic presence of PPAR alpha and with intact LPL hydrolysis. Mass spectrometry reveals that LPL-treatment of either LDL or LDL(-) releases hydroxy-octadecadienoic acids (HODEs), potent PPAR alpha activators. These findings suggest LPL-mediated PPAR alpha activation as an alternative catabolic pathway that may limit inflammatory responses to LDL(-).
authors.affiliation: Cardiovascular Division, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachussetts 02115, USA.
authors.forename: Ouliana
authors.initials: O
authors.lastname: Ziouzenkova
authors.forename: Liana
authors.initials: L
authors.lastname: Asatryan
authors.forename: Deanna
authors.initials: D
authors.lastname: Sahady
authors.forename: Gabriela
authors.initials: G
authors.lastname: Orasanu
authors.forename: Stephan
authors.initials: S
authors.lastname: Perrey
authors.forename: Benjamin
authors.initials: B
authors.lastname: Cutak
authors.forename: Tom
authors.initials: T
authors.lastname: Hassell
authors.forename: Taro E
authors.initials: TE
authors.lastname: Akiyama
authors.forename: Joel P
authors.initials: JP
authors.lastname: Berger
authors.forename: Alex
authors.initials: A
authors.lastname: Sevanian
authors.forename: Jorge
authors.initials: J
authors.lastname: Plutzky
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D004563:Electrochemistry; D006801:Humans; D007249:Inflammation / Q000209:etiology / Q000378:metabolism; D008024:Ligands; D008041:Linoleic Acids / Q000378:metabolism; D008066:Lipolysis; D008071:Lipoprotein Lipase / Q000378:metabolism / Q000494:pharmacology; D008077:Lipoproteins, LDL / Q000737:chemistry / Q000494:pharmacology*; D051379:Mice; D018345:Mice, Knockout; D008954:Models, Biological; D016328:NF-kappa B / Q000378:metabolism; D010084:Oxidation-Reduction; D018160:Receptors, Cytoplasmic and Nuclear / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D014157:Transcription Factors / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D014158:Transcription, Genetic; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology; D019010:Vascular Cell Adhesion Molecule-1 / Q000096:biosynthesis
chemical_list: D008024:Ligands; D008041:Linoleic Acids; D008077:Lipoproteins, LDL; D016328:NF-kappa B; D018160:Receptors, Cytoplasmic and Nuclear; D014157:Transcription Factors; D014409:Tumor Necrosis Factor-alpha; D019010:Vascular Cell Adhesion Molecule-1; D008071:Lipoprotein Lipase