Acidic retinoids synergize with vitamin A to enhance retinol uptake and STRA6, LRAT, and CYP26B1 expression in neonatal lung

Abstract

This article is available online at http://www.jlr.org but unlike VA, which is stored in tissues as retinyl ester (RE) and mobilized to produce RA ( 4 ), no signifi cant amount of RA is stored and the pool of RA turns over rapidly ( 5 ). RA and other retinoids have been shown to enhance alveolar septation in neonatal rats and mice (as reviewed in Refs. 2,3,6,7 ) and in some cases to improve lung repair after injury in adults ( 3,8,9 ). Most of the VA present in the lungs is in the form of RE ( 10-12 ). In fullterm infants, a process of signifi cant RE accumulation in the lungs has begun from the third trimester of fetal life, after which the stored RE becomes quickly depleted during late gestation and early postnatal life ( 10 ). By contrast, preterm infants often have low VA status at birth ( 13-15 ), which may contribute to poor lung maturation and increased susceptibility to respiratory diseases ( 16 ). Therefore, ways to improve RE storage in the lungs in the postnatal period could be useful clinically for supporting retinoid-requiring metabolic functions and aiding postnatal lung development.Previously, we tested a combination of VA (retinol) and RA, referred to as VARA (10:1 molar mixture of VA and RA) as an oral supplement for promoting lung RE formation ( 12 ). Lung RE increased synergistically, at least 4-fold more than for an equal amount of VA alone ( 17 ). As RA is not reduced to retinol in vivo and thus is not a substrate for tissue RE synthesis, the increase in RE in the lungs implies that RA plays a regulatory role in this organ, in some manner facilitating RE formation. The synergistic effect of VARA was selective for the lungs, as RE formation in the liver did not differ between VARA and an equal dose of VA only ( 12,17 ). In a metabolic study using [ 3 H]retinol to trace the uptake of newly absorbed retinol, we found that RA served to direct more of the [ 3 H]retinol tracer and, thus, the oral VA supplement, into the neonatal lung ( 12 ).Abstract Vitamin A (VA) is essential for fetal lung development and postnatal lung maturation. VA is stored mainly as retinyl esters (REs), which may be mobilized for production of retinoic acid (RA). This study was designed 1 ) to evaluate several acidic retinoids for their potential to increase RE in the lungs of VA-supplemented neonatal rats, and 2 ) to determine the expression of retinoid homeostatic genes related to retinol uptake, esterifi cation, and catabolism as possible mechanisms. When neonatal rats were treated with VA combined with any one of several acidic retinoids (RA, 9-cis -RA, or Am580, a stable analog of RA), lung RE increased ‫ف‬ 5-7 times more than after an equal amount of VA alone. Retinol uptake and esterifi cation during the period of absorption correlated with increased expression of both STRA6 (retinol-binding protein receptor) and LRAT (retinol esterifi cation), while a reduction in RE after 12 h in Am580-treated, VA-supplemented rats correlated with a strong and persistent increase in CYP26B1 (RA hydroxylase). We conclude that neona...

Lecithin:Retinol Acyltransferase Is Critical for Cellular Uptake of Vitamin A from Serum Retinol-binding Protein

“…ATRA Regulation of Cellular Vitamin A Uptake-ATRA-dependent regulation of ROL uptake activity by peripheral tissues was recently demonstrated in neonatal lungs of rats (34). Supplementation of animals with ATRA and synthetic analogs resulted in higher RE stores in this tissue.…”

Enzymology of retinoic acid biosynthesis and degradation

“…3 and 175 ). STRA6, the plasma membrane receptor for retinol carrier RBP4, is known to be induced by atRA in extrahepatic tissues ( 173,174 ) while retinolbinding protein receptor 2 (RBPR2), the recently discovered analogous receptor in rodent liver, is suppressed by atRA, presumably to promote the uptake of retinol by extrahepatic tissues under conditions of vitamin A sufficiency ( 176 ).…”

“…Excessive atRA coordinately induces the expression of the components of retinoid storage pathway, including CRBPI, LRAT (170)(171)(172), and retSDR1, which appear to promote the biosynthesis of retinyl esters ( 62 ). At the same time, atRA induces its own catabolism by upregulating CYP26 enzymes ( 173,174 ), which degrade the excessive atRA (reviewed in Refs. 3 and 175 ).…”

Healthy birth weight results in higher vitamin A storage in neonate piglets administered high-dose supplements

“…The low retention in the lung confirms prior studies in rats. 25,27 Supplementing rats with retinyl palmitate alone did not increase fractional uptake of 3 H-VA in lung, but uptake was increased with co-treatment of acidic retinoids. 27 The highest retention in the liver found in the HBW piglets at 24 h (i.e.…”

“…37.4%) was similar to neonatal rats ($40%). 27 The rank of VA concentration in organs analyzed was liver > kidney > adrenal glands > spleen > lung for all treated piglets within one day after dosage. The rank of spleen and lung differed from piglets killed 10 days after supplementation, 21 where lung had a higher retinol concentration than spleen.…”