BACKGROUND AND PURPOSE: 2-Hydroxypropyl-β-cyclodextrin (HPCD) is an FDA approved vehicle for drug delivery and an efficient cholesterol-lowering agent. HPCD was proposed to lower tissue cholesterol via multiple mechanisms including those mediated by oxysterols. CYP27A1 and CYP46A1 are the major oxysterol-producing enzymes in the retina that convert cholesterol to 27- and 24-hydroxycholesterol, respectively. We investigated whether HPCD treatments affected the retina of wild-type and Cyp27a1-/- Cyp46a1-/- mice that do not produce the major retinal oxysterols. EXPERIMENTAL APPROACH: HPCD administration was either by i.p., p.o. or s.c. Delivery to the retina was confirmed by angiography using the fluorescently labelled HPCD. Effects on the levels of retinal sterols, mRNA and proteins were evaluated by GC-MS, qRT-PCR and label-free approach, respectively. KEY RESULTS: In both wild-type and Cyp27a1-/- Cyp46a1-/- mice, HPCD crossed the blood-retinal barrier when delivered i.p. and lowered the retinal cholesterol content when administered p.o. and s.c. In both genotypes, oral HPCD treatment affected the expression of cholesterol-related genes as well as the proteins involved in endocytosis, lysosomal function and lipid homeostasis. Mechanistically, liver X receptors and the altered expression of Lipe (hormone-sensitive lipase), Nceh1 (neutral cholesterol ester hydrolase 1) and NLTP (non-specific lipid-transfer protein) could mediate some of the HPCD effects. CONCLUSIONS AND IMPLICATIONS: HPCD treatment altered retinal cholesterol homeostasis and is a potential therapeutic approach for the reduction of drusen and subretinal drusenoid deposits, cholesterol-rich lesions and hallmarks of age-related macular degeneration. LINKED ARTICLES: This article is part of a themed issue on Oxysterols, Lifelong Health and Therapeutics. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v178.16/issuetoc.
BACKGROUND AND PURPOSE: 2-Hydroxypropyl-β-cyclodextrin (HPCD) is an FDA approved vehicle for drug delivery and an efficient cholesterol-lowering agent. HPCD was proposed to lower tissue cholesterol via multiple mechanisms including those mediated by oxysterols. CYP27A1 and CYP46A1 are the major oxysterol-producing enzymes in the retina that convert cholesterol to 27- and 24-hydroxycholesterol, respectively. We investigated whether HPCD treatments affected the retina of wild-type and Cyp27a1-/- Cyp46a1-/- mice that do not produce the major retinal oxysterols. EXPERIMENTAL APPROACH: HPCD administration was either by i.p., p.o. or s.c. Delivery to the retina was confirmed by angiography using the fluorescently labelled HPCD. Effects on the levels of retinal sterols, mRNA and proteins were evaluated by GC-MS, qRT-PCR and label-free approach, respectively. KEY RESULTS: In both wild-type and Cyp27a1-/- Cyp46a1-/- mice, HPCD crossed the blood-retinal barrier when delivered i.p. and lowered the retinal cholesterol content when administered p.o. and s.c. In both genotypes, oral HPCD treatment affected the expression of cholesterol-related genes as well as the proteins involved in endocytosis, lysosomal function and lipid homeostasis. Mechanistically, liver X receptors and the altered expression of Lipe (hormone-sensitive lipase), Nceh1 (neutral cholesterol ester hydrolase 1) and NLTP (non-specific lipid-transfer protein) could mediate some of the HPCD effects. CONCLUSIONS AND IMPLICATIONS: HPCD treatment altered retinal cholesterol homeostasis and is a potential therapeutic approach for the reduction of drusen and subretinal drusenoid deposits, cholesterol-rich lesions and hallmarks of age-related macular degeneration. LINKED ARTICLES: This article is part of a themed issue on Oxysterols, Lifelong Health and Therapeutics. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v178.16/issuetoc.
Authors: Spyridon Theofilopoulos; William J Griffiths; Peter J Crick; Shanzheng Yang; Anna Meljon; Michael Ogundare; Satish Srinivas Kitambi; Andrew Lockhart; Karin Tuschl; Peter T Clayton; Andrew A Morris; Adelaida Martinez; M Ashwin Reddy; Andrea Martinuzzi; Maria T Bassi; Akira Honda; Tatsuki Mizuochi; Akihiko Kimura; Hiroshi Nittono; Giuseppe De Michele; Rosa Carbone; Chiara Criscuolo; Joyce L Yau; Jonathan R Seckl; Rebecca Schüle; Ludger Schöls; Andreas W Sailer; Jens Kuhle; Matthew J Fraidakis; Jan-Åke Gustafsson; Knut R Steffensen; Ingemar Björkhem; Patrik Ernfors; Jan Sjövall; Ernest Arenas; Yuqin Wang Journal: J Clin Invest Date: 2014-10-01 Impact factor: 14.808
Authors: Joan Gannon; Julia Fernandez-Rodriguez; Hussam Alamri; Shi Bo Feng; Fariba Kalantari; Sarita Negi; Amy H Y Wong; Alexander Mazur; Lennart Asp; Ali Fazel; Ayat Salman; Anthoula Lazaris; Peter Metrakos; John J M Bergeron; Tommy Nilsson Journal: PLoS One Date: 2014-11-14 Impact factor: 3.240
Authors: Demetrios G Vavvas; Anthony B Daniels; Zoi G Kapsala; Jeremy W Goldfarb; Emmanuel Ganotakis; John I Loewenstein; Lucy H Young; Evangelos S Gragoudas; Dean Eliott; Ivana K Kim; Miltiadis K Tsilimbaris; Joan W Miller Journal: EBioMedicine Date: 2016-02-04 Impact factor: 8.143