Mice lacking the Systemic Retinol Transporter RBPR2 are susceptible to Vitamin A Deficiency and show Retinal Phenotypes

Abstract

Purpose : The systemic transport of dietary vitamin A/all-trans retinol/ROL bound to RBP4 into peripheral tissues for storage is an important process that continuously provides chromophore precursors to the retina under fasting conditions, which is necessary for visual function. While the blood transport of the lipophilic vitamin A into the eye is facilitated by the membrane receptor STRA6, the systemic transporter for dietary vitamin A remained elusive. Using a mammalian model, we recently identified retinol binding protein receptor 2 (RBPR2), which has high affinity binding for RBP4 and is critical for systemic ROL uptake and transport to the eye.

Methods : A whole body rbpr2^-/- null mouse line was generated and maintained with vitamin A sufficient and deficient diets. Morphological, immunohistological, HPLC, and electron microscopy studies were performed on rbpr2^-/- mice from 2-8 months of age to evaluate the effects of RBPR2 loss on ocular retinoid content, retinal pathology, and opsin content in photoreceptors. Electroretinography (ERG) analysis was performed to evaluate visual function in rbpr2^-/- and control mice. Spectral optical coherence tomography (OCT) analysis was performed to evaluate the retinal layer thickness.

Results : Rbpr2 knockout mice were viable on both vitamin A sufficient and replete diets. Rbpr2 mice on vitamin A sufficient diets, showed lower ocular retinoid levels, but no significant retinal phenotypes. However, when these mice were placed on vitamin A replete diets, they displayed significantly lower ocular retinoid content, decreased opsins, and significant retinal phenotypes. ERG analysis showed significant decreased visual function in rbpr2^-/- mice on vitamin A sufficient and replete diets.

Conclusions : Our studies of RBPR2 null mice established the importance of the RBPR2 protein for the systemic availability of dietary vitamin A for proper ocular retinoid homeostasis. Under conditions of vitamin A excess and deficiency, our analyses revealed that RBPR2-mediated systemic vitamin A homeostasis is a regulated process that is important for vitamin A transport to the eye when RBP4-ROL constitutes the only transport mode in the fasting condition/vitamin A deficiency. Our findings identifying RBPR2 as a systemic vitamin A transporter have important implications for disease states associated with impaired blood vitamin A homeostasis and visual function.

This abstract was presented at the 2022 ARVO Annual Meeting, held in Denver, CO, May 1-4, 2022, and virtually.