Purchase this article with an account.
Pamela M Martin, Ravirajsinh Jadeja, Bhaumik Pandya, Malita Jones, Ammar Abdelrahman, Folami Lamoke Powell; All eyes on beta-hydroxybutyrate: the impact of local synthesis versus systemic provision on RPE health and function.. Invest. Ophthalmol. Vis. Sci. 2020;61(7):4454.
Download citation file:
© ARVO (1962-2015); The Authors (2016-present)
Dietary modifications such as intermittent fasting (IF) and caloric restriction have been widely reported to impact favorably many tissues and diseases. Elevation of the ketone metabolite beta-hydroxybutyrate (BHB) is the common thread. We were the first to report expression of the BHB receptor, hydroxycarboxylic acid receptor 2 (HCAR2)/GPR109A, in retina. Of late, interest in the effects of BHB in retina has increased. Reports of local BHB synthesis in RPE raise questions regarding not only the mechanisms by which the beneficial effects of BHB are derived but also, the importance of systemically versus locally generated BHB. Here, we evaluated the impact of elevated serum BHB on mitochondrial function, HMGCS2 expression and retinal BHB levels in the presence and absence of HCAR2/GPR109A expression.
Primary human RPE cells were exposed to palmitate/glucose; HMGCS2 expression and BHB levels were monitored. Genes regulating mitochondrial function (PGC-1alpha, Nrf1 and TFAM) and mitochondrial function itself were evaluated in primary human RPE cells following BHB treatment (1mM, 48 h) by qPCR and SeaHorse technology. HMGCS2 expression and BHB levels were evaluated in RPE tissue and primary RPE cells obtained from wildtype (WT) and HCAR2/GPR109A knockout (KO) mice fasted intermittently (IF) or fed ad-libitum (control) for 4 weeks.
Palmitate/glucose treatment confirmed local BHB synthesis by RPE. qPCR and SeaHorse demonstrated significant increases in mitochondrial biogenesis and oxidative phosphorylation and decreased glycolysis in association with BHB treatment. IF increased BHB levels in WT and KO mouse serum and retina but, did not impact HMGCS2 expression in RPE. Although notably, HMGCS2 expression was found to be several fold lower in the absence of HCAR2/GPR109A expression.
BHB improves energy metabolism by stimulating mitochondrial biogenesis and oxidative phosphorylation. This mechanism may underlie the purported robust beneficial effects of BHB in retinal cells and tissue. IF effectively elevates BHB levels in serum and retinal tissue but does not impact HMGCS2 expression in RPE. Thus, while IF/BHB elevation may represent an effective potential strategy for resolving bioenergetic crises in aging and/or diseased RPE, additional studies aimed at understanding the importance of local versus systemically generated BHB are warranted.
This is a 2020 ARVO Annual Meeting abstract.
This PDF is available to Subscribers Only