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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 |
| 顯示於類別: | [化妝品應用與管理系(所)] 期刊論文
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