2-Hydroxypropyl-β-cyclodextrin reduces retinal cholesterol in wild-type and Cyp27a1-/- Cyp46a1-/- mice with deficiency in the oxysterol production.

British Journal of Pharmacology
Nicole El-DarziIrina A Pikuleva

Abstract

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. 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. 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 ...Continue Reading

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Citations

Apr 4, 2021·Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry·Manisha PrajapatiThorsteinn Loftsson
Jul 20, 2021·British Journal of Pharmacology·Mark Nixon, Ruth Andrew

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