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    標題: Lysophosphatidic acid receptor LPA(3) prevents oxidative stress and cellular senescence in Hutchinson-Gilford progeria syndrome
    作者: Chen, Wei-Min
    Chiang, Jui-Chung
    Lin, Yueh-Chien
    Lin, Yu-Nung
    Chuang, Pei-Yun
    Chang, Ya-Chi
    Chien-Chin Chen(陳建欽)
    Wu, Kao-Yi
    Hsieh, Jung-Chien
    Chen, Shih-Kuo
    Huang, Wei-Pang
    Chen, Benjamin P. C.
    Lee, Hsinyu
    貢獻者: Natl Taiwan Univ, Dept Life Sci
    Univ Texas Southwestern Med Ctr Dallas, Dept Radiat Oncol
    Chia Yi Christian Hosp, Ditmanson Med Fdn, Dept Pathol
    Chia Nan Univ Pharm & Sci, Dept Cosmet Sci
    Natl Taiwan Univ, Dept Elect Engn
    Natl Taiwan Univ, Inst Biomed Elect & Bioinformat
    Natl Taiwan Univ, Ctr Biotechnol
    關鍵字: 1-Oleoyl-2-O-methyl-rac-glycerophosphothionate
    cell senescence
    Hutchinson-Gilford progeria syndrome
    LPA(3)
    lysophosphatidic acid
    reactive oxygen species
    日期: 2020-01
    上傳時間: 2020-07-29 13:47:05 (UTC+8)
    出版者: WILEY
    摘要: Hutchinson-Gilford progeria syndrome (HGPS) is a rare laminopathy that produces a mutant form of prelamin A, known as Progerin, resulting in premature aging. HGPS cells show morphological abnormalities of the nuclear membrane, reduced cell proliferation rates, accumulation of reactive oxygen species (ROS), and expression of senescence markers. Lysophosphatidic acid (LPA) is a growth factor-like lipid mediator that regulates various physiological functions via activating multiple LPA G protein-coupled receptors. Here, we study the roles of LPA and LPA receptors in premature aging. We report that the protein level of LPA(3) was highly downregulated through internalization and the lysosomal degradation pathway in Progerin-transfected HEK293 cells. By treating Progerin HEK293 cells with an LPA(3) agonist (OMPT, 1-Oleoyl-2-O-methyl-rac-glycerophosphothionate) and performing shRNA knockdown of the Lpa3r transcript in these cells, we showed that LPA(3) activation increased expression levels of antioxidant enzymes, consequently inhibiting ROS accumulation and ameliorating cell senescence. LPA(3) was shown to be downregulated in HGPS patient fibroblasts through the lysosomal pathway, and it was shown to be crucial for ameliorating ROS accumulation and cell senescence in fibroblasts. Moreover, in a zebrafish model, LPA(3) deficiency was sufficient to cause premature aging phenotypes in multiple organs, as well as a shorter lifespan. Taken together, these findings identify the decline of LPA(3) as a key contributor to the premature aging phenotypes of HGPS cells and zebrafish.
    關聯: Aging Cell, v.19, n.1, e13064
    Appears in Collections:[化妝品應用與管理系(所)] 期刊論文

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