Department of Nutritional Sciences, Pennsylvania State University,University Park, Pennsylvania 16802, USA.
Physiol Genomics. 2011 Jan 7;43(1):57-67. doi: 10.1152/physiolgenomics.00182.2010. Epub 2010 Nov 2.
Vitamin A (retinol) is an essential precursor for the production of retinoic acid (RA), which in turn is a major regulator of gene expression, affecting cell differentiation throughout the body. Understanding how vitamin A nutritional status, as well as therapeutic retinoid treatment, regulates the expression of retinoid homeostatic genes is important for improvement of dietary recommendations and therapeutic strategies using retinoids. This study investigated genes central to processes of retinoid uptake and storage, release to plasma, and oxidation in the liver of rats under steady-state conditions after different exposures to dietary vitamin A (deficient, marginal, adequate, and supplemented) and acutely after administration of a therapeutic dose of all-trans-RA. Over a very wide range of dietary vitamin A, lecithin:retinol acyltransferase (LRAT) as well as multiple cytochrome P-450s (CYP26A1, CYP26B1, and CYP2C22) differed by diet and were highly correlated with one another and with vitamin A status assessed by liver retinol concentration (all correlations, P < 0.05). After acute treatment with RA, the same genes were rapidly and concomitantly induced, preceding retinoic acid receptor (RAR)β, a classical direct target of RA. CYP26A1 mRNA exhibited the greatest dynamic range (change of log 2(6) in 3 h). Moreover, CYP26A1 increased more rapidly in the liver of RA-primed rats than naive rats, evidenced by increased CYP26A1 gene expression and increased conversion of [(3)H]RA to polar metabolites. By in situ hybridization, CYP26A1 mRNA was strongly regulated within hepatocytes, closely resembling retinol-binding protein (RBP)4 in location. Overall, whether RA is produced endogenously from retinol or administered exogenously, changes in retinoid homeostatic gene expression simultaneously favor both retinol esterification and RA oxidation, with CYP26A1 exhibiting the greatest dynamic change.
维生素 A（视黄醇）是视黄酸（RA）产生的必需前体，视黄酸反过来又是基因表达的主要调节剂，影响全身细胞分化。了解维生素 A 营养状况以及治疗性维甲酸治疗如何调节视黄醇稳态基因的表达，对于改善饮食建议和使用维甲酸的治疗策略非常重要。本研究调查了在不同的饮食维生素 A 暴露（缺乏、边缘、充足和补充）和急性给予治疗剂量的全反式-RA 后，处于稳定状态下的大鼠肝脏中与视黄醇摄取和储存、向血浆释放以及氧化相关的核心基因。在非常广泛的饮食维生素 A 范围内，卵磷脂：视黄醇酰基转移酶（LRAT）以及多种细胞色素 P-450（CYP26A1、CYP26B1 和 CYP2C22）因饮食而异，并且彼此高度相关，与肝脏视黄醇浓度评估的维生素 A 状态相关（所有相关性，P < 0.05）。在 RA 急性治疗后，相同的基因迅速并同时被诱导，先于 RA 的经典直接靶标视黄酸受体（RAR）β。CYP26A1 mRNA 表现出最大的动态范围（3 小时内对数 2（6）的变化）。此外，与未处理的大鼠相比，RA 预处理大鼠肝脏中 CYP26A1 的增加更快，这一点可以通过 CYP26A1 基因表达的增加和 [(3)H]RA 向极性代谢物的转化来证明。通过原位杂交，CYP26A1 mRNA 在肝细胞内受到强烈调节，其位置与视黄醇结合蛋白（RBP）4 非常相似。总体而言，无论 RA 是从视黄醇内源性产生还是外源性给予，视黄醇稳态基因表达的变化同时有利于视黄醇酯化和 RA 氧化，CYP26A1 表现出最大的动态变化。
