Impaired retinal function and vitamin A availability in mice lacking retinol-binding protein

Abstract

Retinol-binding protein (RBP) is the sole specific transport protein for retinol (vitamin A) in the circulation, and its single known function is to deliver retinol to tissues. Within tissues, retinol is activated to retinoic acid, which binds to nuclear receptors to regulate transcription of >300 diverse target genes. In the eye, retinol is also activated to 11-cis-retinal, the visual chromophore. We generated RBP knockout mice (RBP -/-) by gene targeting. These mice have several phenotypes. Although viable and fertile, they have reduced blood retinol levels and markedly impaired retinal function during the first months of life. The impairment is not due to developmental retinal defect. Given a vitamin A-sufficient diet, the RBP -/-mice acquire normal vision by 5 months of age even though blood retinol levels remain low. Deprived of dietary vitamin A, vision remains abnormal and blood retinol declines to undetectable levels. Another striking phenotype of the mutant mice is their abnormal retinol metabolism. The RBP -/-mice can acquire hepatic retinol stores, but these cannot be mobilized. Thus, their vitamin A status is extremely tenuous and dependent on a regular vitamin A intake. Unlike wild-type mice, serum retinol levels in adult RBP -/-animals become undetectable after only a week on a vitamin A-deficient diet and their retinal function rapidly deteriorates. Thus RBP is needed for normal vision in young animals and for retinol mobilization in times of insufficient dietary intake, but is otherwise dispensable for the delivery of retinol to tissues.

Retinoids and spermatogenesis: Lessons from mutant mice lacking the plasma retinol binding protein

“…As long as the diet contains ROL (or the ROL precursors), the peripheral extrahepatic tissues build up low stores of RE from circulating RBP-ROL complexes and from ROL precursors embedded in chylomicron remnants and VLDL . Therefore, even though Rbp4-null mice are unable to mobilize their central stores of ROL, they do not develop VAD symptoms provided that their diet contains a source of vitamin A (the present study; Quadro et al, 1999Quadro et al, , 2004aQuadro et al, ,b, 2005Vogel et al, 2002). Along the same lines, when fed a vitamin A-deficient diet, Rbp4-null mutants remain healthy until their peripheral tissue stores are exhausted or at least reach a threshold level below which ROL levels can no longer satisfy the tissue demands.…”

“…Thus, through freeing animals from daily dietary vitamin A intakes in the wild, where vitamin A availability can largely vary along seasons, RBP may have provided an evolutionary advantage accounting for the remarkable conservation of both Rbp4 genomic organization (reviewed in Soprano and Blaner, 1994) and three dimensional structure of the RBP protein (reviewed in Newcomer, 1995). Along the same lines, it is noteworthy that biological functions essential to the permanence of species, such as vision (Quadro et al, 1999, embryonic development (Quadro et al, 2005), and male reproduction (present report) may rely on a vitamin A delivery system, namely ROL-RBP complexes, that is independent on regular dietary vitamin A intakes.…”

“…Compared with WT mice, ROL levels were decreased by 40% in Rbp4 ϩ/LϪ and by 98% in Rbp4-null mice. The trace amounts of circulating ROL in Rbp4-null mice (28 nM vs. 1.7 M in WT mice) are probably accounted for by ROL bound to albumin (Quadro et al, 1999). Low (ϳ10 nM), but similar levels of plasma RP were detected in WT and Rbp4-null mice.…”

“…Altogether, these studies have established that (1) RBP is indispensable to mobilize the hepatic RE stores and, thus, to maintain the plasma concentration of ROL at 1.5 M, notably under conditions of insufficient dietary vitamin A intake (Quadro et al, 1999(Quadro et al, , 2003; (2) RBP is not required for shuttling ROL between hepatocytes and stellate cells (Quadro et al, 2004a); (3) RBP synthesized extrahepatically is not important for recycling ROL to the liver nor to other peripheral tissues (Quadro et al, 2004a); (4) RBP-ROL is the most important delivery source of vitamin A for the retina, which takes up RE from chylomicrons very poorly compared to other tissues Vogel et al, 2002); (5) both maternal and fetal RBP are unable to cross the placenta, indicating that ROL must dissociate from RBP to reach the embryo (Quadro et al, 2004b); (6) RBP-ROL is the most important delivery source of vitamin A for the embryo (Quadro et al, 2005).…”

“…As mice lacking RBP should not mobilize their liver ROL stores (Quadro et al, 1999), we expected that feeding Rbp4-null males a vitamin A-deficient diet would result in a severe state of VAD once these mice have exhausted their testicular stores. Thus, to analyze the spermatogenic alterations occurring during the course of VAD in the mouse, we have generated a Rbp4-null mutant line.…”