title: Oxidized LDL and lysophosphatidylcholine stimulate plasminogen activator inhibitor-1 expression through reactive oxygen species generation and ERK1/2 activation in 3T3-L1 adipocytes.
abstract: Plasminogen activator inhibitor-1 (PAI-1) is secreted from adipose tissue and is considered to be a risk factor for both atherosclerosis and insulin resistance. Here we report for the first time that PAI-1 expression is enhanced by oxidized low-density lipoprotein (OxLDL) and its lipid component lysophosphatidylcholine (LPC) in mouse 3T3-L1 adipocytes. In fully differentiated 3T3-L1 cells, OxLDL treatment increased the mRNA expression and protein secretion of PAI-1 in a dose- and time-dependent manner, whereas native LDL had no effect. The addition of an anti-CD36 antibody suppressed OxLDL-stimulated PAI-1 expression by 50%, suggesting that adipose-derived CD36 contributes to roughly half of the PAI-1 expression stimulated by OxLDL. In addition, pharmacological experiments showed that the OxLDL-stimulated enhancement in PAI-1 expression was mediated through the generation of reactive oxygen species (ROS) and phosphorylation of extracellular signal-regulated kinase 1/2. Furthermore, LPC, a major lipid component of OxLDL, was responsible for the enhanced expression of PAI-1 as phospholipase A(2)-treated acetyl LDL, which generates LPC, strongly stimulated PAI-1 expression, whereas acetyl LDL itself had no such activity. These data demonstrate that the uptake of OxLDL and, in particular, its lipid component LPC into adipocytes triggers aberrant ROS-mediated PAI-1 expression, which may be involved in the pathogenesis of metabolic syndrome.
authors.affiliation: Deparment of Pharmaceutical Biochemistry, Kumamoto University, Kumamoto, Japan. kuniyasu@gpo.kumamotoo-u.ac.jp
authors.forename: Akihiko
authors.initials: A
authors.lastname: Kuniyasu
authors.forename: Mariko
authors.initials: M
authors.lastname: Tokunaga
authors.forename: Takashi
authors.initials: T
authors.lastname: Yamamoto
authors.forename: Shoko
authors.initials: S
authors.lastname: Inoue
authors.forename: Keiko
authors.initials: K
authors.lastname: Obama
authors.forename: Kohichi
authors.initials: K
authors.lastname: Kawahara
authors.forename: Hitoshi
authors.initials: H
authors.lastname: Nakayama
mesh_terms: D041721:3T3-L1 Cells; D017667:Adipocytes / Q000378:metabolism* / Q000473:pathology; D000818:Animals; D000906:Antibodies / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004789:Enzyme Activation / Q000187:drug effects; D005786:Gene Expression Regulation / Q000187:drug effects; D008077:Lipoproteins, LDL / Q000494:pharmacology*; D008244:Lysophosphatidylcholines / Q000494:pharmacology*; D024821:Metabolic Syndrome / Q000378:metabolism / Q000473:pathology; D051379:Mice; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism*; D017395:Plasminogen Activator Inhibitor 1 / Q000096:biosynthesis*; D017382:Reactive Oxygen Species / Q000378:metabolism*; D013997:Time Factors
chemical_list: D000906:Antibodies; D008077:Lipoproteins, LDL; D008244:Lysophosphatidylcholines; D017395:Plasminogen Activator Inhibitor 1; D017382:Reactive Oxygen Species; C099252:oxidized low density lipoprotein; D048052:Mitogen-Activated Protein Kinase 3