Lysophosphatidic acid receptor LPA(3) prevents oxidative stress and cellular senescence in Hutchinson-Gilford progeria syndrome

doi:10.1111/acel.13064

CNU IR > Pharmacy and Science > Dept. of Cosmetic Science and institute of cosmetic science > Periodical Articles > Item 310902800/32489

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Title:	Lysophosphatidic acid receptor LPA(3) prevents oxidative stress and cellular senescence in Hutchinson-Gilford progeria syndrome
Authors:	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
Contributors:	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
Keywords:	1-Oleoyl-2-O-methyl-rac-glycerophosphothionate cell senescence Hutchinson-Gilford progeria syndrome LPA(3) lysophosphatidic acid reactive oxygen species
Date:	2020-01
Issue Date:	2020-07-29 13:47:05 (UTC+8)
Publisher:	WILEY
Abstract:	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.
Relation:	Aging Cell, v.19, n.1, e13064
Appears in Collections:	[Dept. of Cosmetic Science and institute of cosmetic science] Periodical Articles

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