Lysophosphatidic acid receptor LPA3 prevents oxidative stress and cellular senescence in Hutchinson–Gilford progeria syndrome

Wei Min Chen, Jui Chung Chiang, Yueh Chien Lin, Yu Nung Lin, Pei Yun Chuang, Ya Chi Chang, Chien Chin Chen, Kao Yi Wu, Jung Chien Hsieh, Shih Kuo Chen, Wei Pang Huang, Benjamin P.C. Chen, Hsinyu Lee

Research output: Contribution to journalArticle

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 LPA3 was highly downregulated through internalization and the lysosomal degradation pathway in Progerin-transfected HEK293 cells. By treating Progerin HEK293 cells with an LPA3 agonist (OMPT, 1-Oleoyl-2-O-methyl-rac-glycerophosphothionate) and performing shRNA knockdown of the Lpa3r transcript in these cells, we showed that LPA3 activation increased expression levels of antioxidant enzymes, consequently inhibiting ROS accumulation and ameliorating cell senescence. LPA3 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, LPA3 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 LPA3 as a key contributor to the premature aging phenotypes of HGPS cells and zebrafish.

Original languageEnglish (US)
Article numbere13064
JournalAging Cell
DOIs
Publication statusAccepted/In press - Jan 1 2019

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Keywords

  • 1-Oleoyl-2-O-methyl-rac-glycerophosphothionate
  • cell senescence
  • Hutchinson–Gilford progeria syndrome
  • LPA
  • lysophosphatidic acid
  • reactive oxygen species

ASJC Scopus subject areas

  • Aging
  • Cell Biology

Cite this

Chen, W. M., Chiang, J. C., Lin, Y. C., Lin, Y. N., Chuang, P. Y., Chang, Y. C., ... Lee, H. (Accepted/In press). Lysophosphatidic acid receptor LPA3 prevents oxidative stress and cellular senescence in Hutchinson–Gilford progeria syndrome. Aging Cell, [e13064]. https://doi.org/10.1111/acel.13064