Loss of the vitamin A receptor RBPR2 in mice disrupts whole-body retinoid homeostasis and the quantitative balance regulating retinylidene protein synthesis

The distribution of stored dietary vitamin A/all-trans-retinol (ROL) from the liver throughout the body is critical for maintaining retinoid function in peripheral tissues and for generating visual pigments for photoreceptor cell function. ROL circulates in the blood bound to the retinol binding protein 4 (RBP4) as RBP4-ROL. Two membrane receptors, RBPR2 in the liver and other non-ocular tissues, and STRA6 in the eye are proposed to bind circulatory RBP4 and this mechanism facilitates the internalization of ROL. Herein, we conducted a longitudinal study to investigate the importance of RBPR2 and influence of vitamin A content in the diet on whole-body retinoid homeostasis and its effects on chromophore production in the support of visual function. Rbpr2-knockout (Rbpr2^−/−) and wild-type mice were fed a vitamin A sufficient (VAS) or a vitamin A deficient (VAD) diet. After 3-months of dietary intervention and compared with WT mice, Rbpr2^−/− mice showed significantly lower hepatic ROL and retinyl ester content, and decreased chromophore concentrations, manifesting in dysfunctional scotopic and photopic electroretinogram (ERG) responses. These phenotypes were more severe in VAD Rbpr2^−/− mice, when compared with VAS Rbpr2^−/− mice. After 6 months of dietary intervention, while WT mice were able to maintain retinoid homeostasis in peripheral tissues, Rbpr2^−/− mice showed elevated serum apo-RBP4 protein, decreased retinoid content in peripheral tissues including the liver and the eye causing an accumulation of apoprotein opsin in photoreceptors, which resulted in delayed rod and cone opsin regeneration. Together, our analyses characterize the molecular events underlying nutritional blindness in a novel mouse model and indicate that the vitamin A receptor, RBPR2, is required for whole-body retinoid homeostasis, which supports chromophore production and visual function under variable conditions of dietary vitamin A intake throughout the lifespan of the animal.