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Activation of LXRs Reduces Oxysterol Lipotoxicity in RPE Cells by Promoting Mitochondrial Function

Lirong Xie1,2, Qing Gu1,2, Xingwei Wu1,2

  • 1Department of Ophthalmology, Shanghai General Hospital (Shanghai First People's Hospital), Shanghai Jiao Tong University School of Medicine, Shanghai 200080, China.

Nutrients
|June 24, 2022
PubMed

Insights

Liver X receptors (LXRs) activation combats lipotoxicity and apoptosis in retinal cells, offering a promising therapeutic strategy for dry age-related macular degeneration (AMD). This research highlights LXRs

Area of Science:

  • Ophthalmology and Molecular Biology
  • Neurodegenerative Diseases
  • Lipid Metabolism and Inflammation

Background:

  • Age-related macular degeneration (AMD) is a leading cause of blindness with limited treatments.
  • Genetic studies link lipid metabolism and inflammation to AMD pathogenesis.
  • The role of Liver X receptors (LXRs) in AMD and their mechanisms are not well understood.

Purpose of the Study:

  • To investigate the impact of lipotoxicity on retinal pigmental epithelial (ARPE-19) cells.
  • To evaluate the efficacy of LXRs in mitigating 7-ketocholesterol (7KCh) induced lipotoxicity in retinal pigment epithelial (RPE) cells.
  • To elucidate the molecular mechanisms by which LXRs exert protective effects in AMD models.

Main Methods:

  • Utilized in vitro models with ARPE-19 cells and in vivo mouse models.
  • Assessed the effects of LXR activation on oxidative lipid accumulation and RPE cell apoptosis induced by oxysterols.
  • Measured mitochondrial membrane potential and key proteins involved in mitophagy (p62, mTOR, LC3I/II) in response to LXR modulation.

Main Results:

  • LXR activation decreased oxidative lipid accumulation in mouse retinas and ARPE-19 cells.
  • LXR agonists protected RPE cells from oxysterol-induced apoptosis and restored mitochondrial membrane potential.
  • Activating LXRs upregulated mitophagy-related proteins (p62, mTOR, LC3I/II), while LXR knockdown had the opposite effect.

Conclusions:

  • LXR activation effectively reduces lipotoxicity and oxysterol-induced damage in RPE cells.
  • LXRs promote mitophagy, a cellular process crucial for maintaining RPE health.
  • LXR-targeting pharmaceuticals represent a potential therapeutic avenue for dry AMD.
Keywords:
age-related macular degenerationlipid metabolismlipotoxicityliver X receptorsmitochondrial function

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