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Rui Cheng, Elizabeth P Moran, Kelu Zhou, Marin Gantner, Jian-Xing (Jay) Ma; Role of PPAR-alpha in Retinal Mitochondrial Function. Invest. Ophthalmol. Vis. Sci. 2017;58(8):3020.
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The retina is one of the highest energy-consuming tissues in the body. Glucose and lipid are important substrates for retinal ATP production. Peroxisome proliferator-activated receptor alpha (PPARα) is a nuclear receptor regulating fatty acid oxidation (FAO), and PPARα agonists have beneficial effects in retinal diseases of metabolic origin. However, the role of PPARα in retinal energy metabolism remains incompletely understood. This study tested the hypothesis that PPARα is essential for retinal energy metabolism.
PPARα-deficient (PPARα-/-) mice and age and genetic background-matched wild-type (Wt) mice were euthanized. Retinas were freshly dissected. Oxygen consumption rates (OCR) and extracellular acidification rates (ECAR) in response to energy substrates glucose, pyruvate or palmitate were measured using a Seahorse XFe96 Flux Analyzer®. A two-tailed, unpaired Student’s t-test was used for statistical analysis.
Palmitate increased OCR in Wt retinas at the age of 4 weeks, but did not change OCR in PPARα-/- retinas, suggesting impaired FAO in the absence of PPARα. To determine if impaired FAO affected glucose metabolism, we measured retinal OCR and ECAR in response to glucose. High glucose decreased the maximal OCR and increased ECAR in 4-week old Wt retinas, suggesting that an abundance of glucose promoted a shift towards glycolytic metabolism. However, although glucose increased ECAR in PPARα-/- retinas, it did not affect maximal OCR, indicating that more glycolytic products may be used for oxidative metabolism in the absence of PPARα. Accordingly, we found that pyruvate did not significantly affect OCR in Wt retinas, but did increase OCR in PPARα-/- retinas. We further compared mitochondrial function with aging in PPARα-/- retinas by measuring OCR at 4, 8 and 12 weeks of age. We found that beginning at 8 weeks of age, basal and maximal OCR were decreased, and further declined at 12 weeks, suggesting that PPARα deficiency leads to mitochondrial dysfunction.
Endogenous PPARα is essential for retinal energy metabolism. Diabetes-induced PPARα down-regulation may contribute to disturbed energy metabolism in the retina.
This is an abstract that was submitted for the 2017 ARVO Annual Meeting, held in Baltimore, MD, May 7-11, 2017.
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