title: Lipoprotein-associated lysolipids are differentially involved in high-density lipoprotein- and its oxidized form-induced neurite remodeling in PC12 cells.
abstract: Oxidatively damaged proteins and lipid peroxidation products have been shown to accumulate in the brain of neurodegenerative diseases, such as Alzheimer's disease and multiple sclerosis, and oxidized lipoprotein is considered to be toxic and neurodegenerative. However, the role of lipoprotein and its oxidized form in neurite remodeling has not been well understood. In the present study, we have aimed to clarify whether and, if so, how high-density lipoprotein (HDL) and oxidized HDL (oxHDL) affect neuritogenesis. In the presence of nerve growth factor, exposure of PC12 cells to either HDL or oxHDL induces a rapid neurite retraction, which is followed by re-outgrowth of neurites in either case; however, oxHDL-treated cells exhibit much longer outgrowths than do basal and HDL-treated cells. Thus, processes in the morphological changes of neuronal cells after lipoprotein treatment are composed of two phases: the reversible retraction phase and the extension phase. Characterization of the active fractions of lipids and experiments with desensitization and knockdown of receptors have indicated that the reversible retraction phase involves mainly sphingosine 1-phosphate for HDL and lysophosphatidic acid for oxHDL. The change in the components responsible for the retraction response is comparable with the change in sphingosine 1-phosphate and lysophosphatidic acid contents by the oxidation of HDL. In the extension phase, lysophosphatidylcholine, which is increased by the oxidation of HDL, may play a stimulatory role in neurite outgrowth. We conclude that lipoprotein and its oxidized form differentially regulate neuritogenesis through lipoprotein-associated lysolipid molecules.
authors.affiliation: Laboratory of Signal Transduction, Institute for Molecular and Cellular Regulation, Gunma University, Maebashi 371-8512, Japan. Electronic address: kosato@gunma-u.ac.jp.
authors.forename: Koichi
authors.initials: K
authors.lastname: Sato
authors.affiliation: Laboratory of Signal Transduction, Institute for Molecular and Cellular Regulation, Gunma University, Maebashi 371-8512, Japan.
authors.forename: Masayuki
authors.initials: M
authors.lastname: Tobo
authors.affiliation: Laboratory of Signal Transduction, Institute for Molecular and Cellular Regulation, Gunma University, Maebashi 371-8512, Japan.
authors.forename: Chihiro
authors.initials: C
authors.lastname: Mogi
authors.affiliation: Laboratory of Signal Transduction, Institute for Molecular and Cellular Regulation, Gunma University, Maebashi 371-8512, Japan.
authors.forename: Naoya
authors.initials: N
authors.lastname: Murata
authors.affiliation: Laboratory of Signal Transduction, Institute for Molecular and Cellular Regulation, Gunma University, Maebashi 371-8512, Japan.
authors.forename: Mie
authors.initials: M
authors.lastname: Kotake
authors.affiliation: Department of Nursing, Faculty of Health Care, Takasaki University of Health and Welfare, Takasaki 370-0033, Japan.
authors.forename: Atsushi
authors.initials: A
authors.lastname: Kuwabara
authors.affiliation: Laboratory of Pharmacology, College of Pharmacy, Pusan National University, Busan 609-735, Republic of Korea.
authors.forename: Dong-Soon
authors.initials: DS
authors.lastname: Im
authors.affiliation: Laboratory of Signal Transduction, Institute for Molecular and Cellular Regulation, Gunma University, Maebashi 371-8512, Japan. Electronic address: okajima@gunma-u.ac.jp.
authors.forename: Fumikazu
authors.initials: F
authors.lastname: Okajima
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D006801:Humans; D008075:Lipoproteins, HDL / Q000378:metabolism*; D008246:Lysophospholipids / Q000378:metabolism; D009414:Nerve Growth Factors / Q000378:metabolism*; D016501:Neurites / Q000378:metabolism*; D010084:Oxidation-Reduction; D016716:PC12 Cells; D051381:Rats
chemical_list: D008075:Lipoproteins, HDL; D008246:Lysophospholipids; D009414:Nerve Growth Factors; C032881:lysophosphatidic acid
keywords: High-density lipoprotein; Lysophosphatidic acid; Neurite remodeling; Oxidation; PC12 cell; Sphingosine 1-phospahte