PMID- 29183319
OWN - NLM
STAT- MEDLINE
DCOM- 20180629
LR  - 20181113
IS  - 1741-7007 (Electronic)
IS  - 1741-7007 (Linking)
VI  - 15
IP  - 1
DP  - 2017 Nov 28
TI  - PPARalpha is essential for retinal lipid metabolism and neuronal survival.
PG  - 113
LID - 10.1186/s12915-017-0451-x [doi]
LID - 113
AB  - BACKGROUND: Peroxisome proliferator activated receptor-alpha (PPARalpha) is a 
      ubiquitously expressed nuclear receptor. The role of endogenous PPARalpha in retinal 
      neuronal homeostasis is unknown. Retinal photoreceptors are the highest 
      energy-consuming cells in the body, requiring abundant energy substrates. PPARalpha 
      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 PPARalpha is essential for the 
      maintenance and survival of retinal neurons, with Pparalpha (-/-) mice developing 
      retinal degeneration first detected at 8 weeks of age. Using extracellular flux 
      analysis, we identified that PPARalpha mediates retinal utilization of lipids as an 
      energy substrate, and that ablation of PPARalpha ultimately results in retinal 
      bioenergetic deficiency and neurodegeneration. This may be due to PPARalpha 
      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 PPARalpha in retinal neuronal survival 
      and lipid metabolism, and furthermore underscore the importance of fatty acid 
      oxidation in photoreceptor survival. We also suggest PPARalpha as a putative 
      therapeutic target for age-related macular degeneration, which may be due in part 
      to decreased mitochondrial efficiency and subsequent energetic deficits.
FAU - Pearsall, Elizabeth A
AU  - Pearsall EA
AD  - Department of Ophthalmology, Boston Children's Hospital, Harvard Medical School, 
      Boston, MA, 02115, USA.
AD  - Department of Physiology, University of Oklahoma Health Sciences Center, 941 
      Stanton L. Young Blvd., BSEB 328B, Oklahoma City, OK, 73104, USA.
FAU - Cheng, Rui
AU  - Cheng R
AD  - Department of Physiology, University of Oklahoma Health Sciences Center, 941 
      Stanton L. Young Blvd., BSEB 328B, Oklahoma City, OK, 73104, USA.
FAU - Zhou, Kelu
AU  - Zhou K
AD  - Department of Physiology, University of Oklahoma Health Sciences Center, 941 
      Stanton L. Young Blvd., BSEB 328B, Oklahoma City, OK, 73104, USA.
FAU - Takahashi, Yusuke
AU  - Takahashi Y
AD  - Department of Physiology, University of Oklahoma Health Sciences Center, 941 
      Stanton L. Young Blvd., BSEB 328B, Oklahoma City, OK, 73104, USA.
AD  - Section of Diabetes and Endocrinology, Department of Medicine, University of 
      Oklahoma Health Sciences Center, Oklahoma City, OK, 73104, USA.
FAU - Matlock, H Greg
AU  - Matlock HG
AD  - Department of Physiology, University of Oklahoma Health Sciences Center, 941 
      Stanton L. Young Blvd., BSEB 328B, Oklahoma City, OK, 73104, USA.
FAU - Vadvalkar, Shraddha S
AU  - Vadvalkar SS
AD  - Aging and Metabolism Research Program, Oklahoma Medical Research Foundation, 
      Oklahoma City, OK, 73104, USA.
FAU - Shin, Younghwa
AU  - Shin Y
AD  - Department of Physiology, University of Oklahoma Health Sciences Center, 941 
      Stanton L. Young Blvd., BSEB 328B, Oklahoma City, OK, 73104, USA.
FAU - Fredrick, Thomas W
AU  - Fredrick TW
AD  - Department of Ophthalmology, Boston Children's Hospital, Harvard Medical School, 
      Boston, MA, 02115, USA.
FAU - Gantner, Marin L
AU  - Gantner ML
AD  - The Lowy Medical Research Institute, La Jolla, CA, 92037, USA.
FAU - Meng, Steven
AU  - Meng S
AD  - Department of Ophthalmology, Boston Children's Hospital, Harvard Medical School, 
      Boston, MA, 02115, USA.
FAU - Fu, Zhongjie
AU  - Fu Z
AD  - Department of Ophthalmology, Boston Children's Hospital, Harvard Medical School, 
      Boston, MA, 02115, USA.
FAU - Gong, Yan
AU  - Gong Y
AD  - Department of Ophthalmology, Boston Children's Hospital, Harvard Medical School, 
      Boston, MA, 02115, USA.
FAU - Kinter, Michael
AU  - Kinter M
AD  - Aging and Metabolism Research Program, Oklahoma Medical Research Foundation, 
      Oklahoma City, OK, 73104, USA.
FAU - Humphries, Kenneth M
AU  - Humphries KM
AD  - Aging and Metabolism Research Program, Oklahoma Medical Research Foundation, 
      Oklahoma City, OK, 73104, USA.
FAU - Szweda, Luke I
AU  - Szweda LI
AD  - Aging and Metabolism Research Program, Oklahoma Medical Research Foundation, 
      Oklahoma City, OK, 73104, USA.
FAU - Smith, Lois E H
AU  - Smith LEH
AD  - Department of Ophthalmology, Boston Children's Hospital, Harvard Medical School, 
      Boston, MA, 02115, USA.
FAU - Ma, Jian-Xing
AU  - Ma JX
AD  - Department of Physiology, University of Oklahoma Health Sciences Center, 941 
      Stanton L. Young Blvd., BSEB 328B, Oklahoma City, OK, 73104, USA. 
      jian-xing-ma@ouhsc.edu.
AD  - Section of Diabetes and Endocrinology, Department of Medicine, University of 
      Oklahoma Health Sciences Center, Oklahoma City, OK, 73104, USA. 
      jian-xing-ma@ouhsc.edu.
LA  - eng
GR  - R01 HL125625/HL/NHLBI NIH HHS/United States
GR  - P20 GM103639/GM/NIGMS NIH HHS/United States
GR  - R01 EY017017/EY/NEI NIH HHS/United States
GR  - GM103639/National Institutes of Health/
GR  - 3-PDF-2014-107-A-N/Juvenile Diabetes Research Foundation International/
GR  - 2-SRA-2014-147-Q-R/JDRF/United States
GR  - R01 EY018659/EY/NEI NIH HHS/United States
GR  - P30 GM122744/GM/NIGMS NIH HHS/United States
GR  - P30 EY021725/EY/NEI NIH HHS/United States
GR  - P20 GM104934/GM/NIGMS NIH HHS/United States
GR  - P30 HD018655/HD/NICHD NIH HHS/United States
GR  - P30 AG050911/AG/NIA NIH HHS/United States
GR  - EY021725/National Eye Institute/
GR  - HL125625/National Heart, Lung, and Blood Institute/
GR  - R01 EY012231/EY/NEI NIH HHS/United States
GR  - U54 HD090255/HD/NICHD NIH HHS/United States
GR  - R01 EY019309/EY/NEI NIH HHS/United States
GR  - EY019309/National Eye Institute/
GR  - 305485 PREVENT-ROP/European Commission/
GR  - GM104934/National Institutes of Health/
GR  - P20GM104934/National Institutes of Health/
GR  - EY018659/National Eye Institute/
GR  - R01 EY005318/EY/NEI NIH HHS/United States
GR  - R24 EY024864/EY/NEI NIH HHS/United States
GR  - HD18655/National Institutes of Health/
PT  - Journal Article
DEP - 20171128
PL  - England
TA  - BMC Biol
JT  - BMC biology
JID - 101190720
RN  - 0 (Fatty Acids)
RN  - 0 (PPAR alpha)
SB  - IM
MH  - Animals
MH  - Fatty Acids/*metabolism
MH  - *Lipid Metabolism
MH  - Mice
MH  - Mice, Inbred C57BL
MH  - Oxidation-Reduction
MH  - PPAR alpha/*genetics/metabolism
MH  - Rats
MH  - Rats, Sprague-Dawley
MH  - Retina/*metabolism
MH  - Retinal Neurons/*physiology
PMC - PMC5706156
OTO - NOTNLM
OT  - Age-related macular degeneration
OT  - Fatty acid oxidation
OT  - Lipids
OT  - Mitochondria
OT  - Neurodegeneration
OT  - Retina
OT  - Retinal energy metabolism
COIS- All animal studies were performed in compliance with the NIH guidelines for the 
      Care and Use of Animals, and approved by the Institutional Animal Care and Use 
      Committees at the University of Oklahoma Health Sciences Center and Boston 
      Children's Hospital. COMPETING INTERESTS: The authors declare that they have no 
      competing interests. PUBLISHER'S NOTE: Springer Nature remains neutral with 
      regard to jurisdictional claims in published maps and institutional affiliations.
EDAT- 2017/12/01 06:00
MHDA- 2018/06/30 06:00
PMCR- 2017/11/28
CRDT- 2017/11/30 06:00
PHST- 2017/06/03 00:00 [received]
PHST- 2017/11/06 00:00 [accepted]
PHST- 2017/11/30 06:00 [entrez]
PHST- 2017/12/01 06:00 [pubmed]
PHST- 2018/06/30 06:00 [medline]
PHST- 2017/11/28 00:00 [pmc-release]
AID - 10.1186/s12915-017-0451-x [pii]
AID - 451 [pii]
AID - 10.1186/s12915-017-0451-x [doi]
PST - epublish
SO  - BMC Biol. 2017 Nov 28;15(1):113. doi: 10.1186/s12915-017-0451-x.