PDF(Pubmed)
Abstract：
The distribution of dietary vitamin A/all-trans retinol (ROL) 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 STRA6 in the eye are proposed to bind circulatory RBP4 and this mechanism is critical for internalizing ROL into cells. Here, we present a longitudinal investigation towards the importance of RBPR2 and influence of the diet on systemic retinoid homeostasis for visual function. Age matched Rbpr2-KO (Rbpr2 -/- ) and wild-type (WT) mice were fed either a vitamin A sufficient (VAS) or a vitamin A deficient (VAD) diet. At 3- and 6-months, we performed retinoid quantification of ocular and non-ocular tissues using HPLC analysis and complemented the data with visual physiology, rhodopsin quantification by spectrophotometry, and biochemical analysis. At 3-months and compared to WT mice, Rbpr2 -/- mice fed either vitamin A diets displayed lower scotopic and photopic electroretinogram (ERG) responses, which correlated with HPLC analysis that revealed Rbpr2 -/- mice had significantly lower hepatic and ocular retinoid content. Interestingly, with the exception of the liver, long-term feeding of Rbpr2 -/- mice with a VAS diet promoted all-trans retinol accumulation in most peripheral tissues. However, even under VAS dietary conditions significant amounts of unliganded opsins in rods, together with decreased visual responses were evident in aged mice lacking RBPR2, when compared to WT mice. Together, our analyses characterize the molecular events underlying nutritional blindness in a novel mouse model and indicate that loss of the liver specific RBP4-ROL receptor, RBPR2, influences systemic retinoid homeostasis and rhodopsin synthesis, which causes profound visual function defects under severe vitamin A deficiency conditions.
摘要：
膳食维生素A/全反式视黄醇(ROL)在整个身体中的分布对于维持外周组织中的类视黄醇功能和产生感光细胞功能的视觉色素是关键的。ROL在与视黄醇结合蛋白4(RBP4)结合的血液中循环为RBP4-ROL。两个膜受体,建议肝脏中的RBPR2和眼睛中的STRA6结合循环RBP4，并且该机制对于将ROL内化到细胞中至关重要。这里,我们对RBPR2的重要性以及饮食对全身类视黄醇稳态对视功能的影响进行了纵向研究.年龄匹配的Rbpr2-KO(Rbpr2-/-)和野生型(WT)小鼠被饲喂维生素A充足(VAS)或维生素A缺乏(VAD)饮食。在3个月和6个月时，我们使用HPLC分析对眼和非眼组织进行类维生素A定量，并用视觉生理学补充数据，通过分光光度法对视紫红质进行定量，和生化分析。在3个月时，与WT小鼠相比，饲喂维生素A饮食的Rbpr2-/-小鼠显示出较低的暗视和明视视网膜电图（ERG）反应，与HPLC分析相关，显示Rbpr2-/-小鼠的肝脏和眼部类维生素A含量显着降低。有趣的是,除了肝脏,用VAS饮食长期喂养Rbpr2-/-小鼠促进全反式视黄醇在大多数外周组织中的积累。然而,即使在VAS饮食条件下，杆状物中仍有大量未结合的视蛋白，与WT小鼠相比，缺乏RBPR2的老年小鼠的视觉反应明显减少。一起,我们的分析表征了新小鼠模型中营养盲的分子事件，并表明肝脏特异性RBP4-ROL受体的丢失，RBPR2，影响全身类视黄醇稳态和视紫红质合成，在严重的维生素A缺乏情况下导致严重的视觉功能缺陷。
