PPARα is essential for retinal lipid metabolism and neuronal survival

Elizabeth A. Pearsall, Rui Cheng, Kelu Zhou, Yusuke Takahashi, H. Greg Matlock, Shraddha S. Vadvalkar, Younghwa Shin, Thomas W. Fredrick, Marin L. Gantner, Steven Meng, Zhongjie Fu, Yan Gong, Michael Kinter, Kenneth M. Humphries, Luke I. Szweda, Lois E.H. Smith, Jian xing Ma

Research output: Contribution to journalArticlepeer-review

22 Scopus citations

Abstract

Background: Peroxisome proliferator activated receptor-alpha (PPARα) is a ubiquitously expressed nuclear receptor. The role of endogenous PPARα in retinal neuronal homeostasis is unknown. Retinal photoreceptors are the highest energy-consuming cells in the body, requiring abundant energy substrates. PPARα is a known regulator of lipid metabolism, and we hypothesized that it may regulate lipid use for oxidative phosphorylation in energetically demanding retinal neurons. Results: We found that endogenous PPARα is essential for the maintenance and survival of retinal neurons, with Pparα -/- mice developing retinal degeneration first detected at 8 weeks of age. Using extracellular flux analysis, we identified that PPARα mediates retinal utilization of lipids as an energy substrate, and that ablation of PPARα ultimately results in retinal bioenergetic deficiency and neurodegeneration. This may be due to PPARα regulation of lipid transporters, which facilitate the internalization of fatty acids into cell membranes and mitochondria for oxidation and ATP production. Conclusion: We identify an endogenous role for PPARα in retinal neuronal survival and lipid metabolism, and furthermore underscore the importance of fatty acid oxidation in photoreceptor survival. We also suggest PPARα as a putative therapeutic target for age-related macular degeneration, which may be due in part to decreased mitochondrial efficiency and subsequent energetic deficits.

Original languageEnglish (US)
Article number113
JournalBMC Biology
Volume15
Issue number1
DOIs
StatePublished - Nov 28 2017

Keywords

  • Age-related macular degeneration
  • Fatty acid oxidation
  • Lipids
  • Mitochondria
  • Neurodegeneration
  • Retina
  • Retinal energy metabolism

ASJC Scopus subject areas

  • Biotechnology
  • Structural Biology
  • Ecology, Evolution, Behavior and Systematics
  • Physiology
  • Biochemistry, Genetics and Molecular Biology(all)
  • Agricultural and Biological Sciences(all)
  • Plant Science
  • Developmental Biology
  • Cell Biology

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