title: Lipolysis of triglyceride-rich lipoproteins generates PPAR ligands: evidence for an antiinflammatory role for lipoprotein lipase.
abstract: Increased levels of triglyceride-rich lipoproteins provoke lipid accumulation in the artery wall, triggering early inflammatory responses central to atherosclerosis like endothelial adhesion molecule expression. The endogenous mechanisms limiting such reactions remain poorly defined. Lipoprotein lipase (LPL) plays a central role in lipid metabolism by hydrolyzing triglyceride rich lipoproteins and releasing fatty acids. We found that LPL treatment reversed tumor necrosis factor alpha and very low-density lipoprotein (VLDL)-stimulated endothelial vascular cell adhesion molecule 1 (VCAM1) induction and VCAM1 promoter responses, thus recapitulating effects reported with synthetic peroxisome proliferator-activated receptor (PPAR) agonists. In fact, these LPL effects on VCAM1 were absent in endothelial cells isolated from PPAR alpha-deficient mice. This finding suggests a novel antiinflammatory role for LPL. Further studies reveal specificity for PPAR activation through lipolysis in regards to lipoprotein substrate (VLDL >> LDL > HDL), PPAR isoform (PPAR alpha >> PPAR delta > PPAR gamma), and among fatty acid-releasing lipases. These PPAR responses required intact LPL catalytic activity. In vivo, transgenic mice overexpressing LPL had increased peroxisome proliferation, but not in the genetic absence of PPAR alpha. Although human plasma possesses minimal PPAR alpha activation despite containing abundant free fatty acids, marked PPAR alpha activation is seen with human plasma after LPL is added in vitro or systemically released in vivo. These data suggest a previously uncharacterized pathway in which the key lipolytic enzyme LPL can act on circulating lipoproteins to generate PPAR alpha ligands, providing a potentially important link between lipoprotein metabolism and distal PPAR alpha transcriptional effects.
authors.affiliation: Cardiovascular Division, Brigham and Women's Hospital, Harvard University, Boston, MA 02115, USA.
authors.forename: Ouliana
authors.initials: O
authors.lastname: Ziouzenkova
authors.forename: Stephane
authors.initials: S
authors.lastname: Perrey
authors.forename: Liana
authors.initials: L
authors.lastname: Asatryan
authors.forename: Juliana
authors.initials: J
authors.lastname: Hwang
authors.forename: Karen L
authors.initials: KL
authors.lastname: MacNaul
authors.forename: David E
authors.initials: DE
authors.lastname: Moller
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Rader
authors.forename: Alex
authors.initials: A
authors.lastname: Sevanian
authors.forename: Rudolf
authors.initials: R
authors.lastname: Zechner
authors.forename: Gerald
authors.initials: G
authors.lastname: Hoefler
authors.forename: Jorge
authors.initials: J
authors.lastname: Plutzky
mesh_terms: D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology*; D015152:Blotting, Northern; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D005227:Fatty Acids / Q000378:metabolism; D006801:Humans; D007150:Immunohistochemistry; D008024:Ligands; D050356:Lipid Metabolism; D008066:Lipolysis; D008071:Lipoprotein Lipase / Q000502:physiology*; D008074:Lipoproteins / Q000378:metabolism*; D008079:Lipoproteins, VLDL / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D008856:Microscopy, Fluorescence; D008954:Models, Biological; D020033:Protein Isoforms; D018160:Receptors, Cytoplasmic and Nuclear / Q000235:genetics / Q000378:metabolism*; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D014158:Transcription, Genetic; D014162:Transfection; D014280:Triglycerides / Q000378:metabolism*; D019010:Vascular Cell Adhesion Molecule-1 / Q000378:metabolism
chemical_list: D000893:Anti-Inflammatory Agents; D005227:Fatty Acids; D008024:Ligands; D008074:Lipoproteins; D008079:Lipoproteins, VLDL; D020033:Protein Isoforms; D018160:Receptors, Cytoplasmic and Nuclear; D014157:Transcription Factors; D014280:Triglycerides; D019010:Vascular Cell Adhesion Molecule-1; D008071:Lipoprotein Lipase