Retinoid Homeostatic Gene Expression in Liver, Lung and Kidney: Ontogeny and Response to Vitamin A-Retinoic Acid (VARA) Supplementation from Birth to Adult Age.

Sarah A Owusu,A Catharine Ross,Michael Schubert

doi:10.1371/journal.pone.0145924

Abstract

Vitamin A (VA, retinol) metabolism is homeostatically controlled, but little is known of its regulation in the postnatal period. Here, we determined the postnatal trajectory of VA storage and metabolism in major compartments of VA metabolism–plasma, liver, lung, and kidney from postnatal (P) day 1 to adulthood. We also investigated the response to supplementation with VARA, a combination of VA and 10% all-trans-retinoic acid that previously was shown to synergistically increase retinol uptake and storage in lung. Nursling pups of dams fed a VA-marginal diet received an oral dose of oil (placebo) or VARA on each of four neonatal days: P1, P4, P7, and P10; and again as adults. Tissues were collected 6 h after the final dosing on P1, P4, P10, and at adult age. Gene transcripts for Lrat and Rbp4 in liver and Raldh-1 and Raldh-3 in lung, did not differ in the neonatal period but were higher, P<0.05, in adults, while Cyp26B1, Stra6, megalin, and Raldh-2 in lung did not differ from perinatal to adult ages. VARA supplementation increased total retinol in plasma, liver and lung, with a dose-by-dose accumulation in neonatal liver and lung, while transcripts for Lrat in liver, megalin in kidney, Cyp26A1/B1 in liver and lung, respectively, and Stra6 in lung, were all increased, suggesting pathways of VA uptake, storage and RA oxidation were each augmented after VARA. VARA decreased hepatic expression of Rbp4, responsible for VA trafficking from liver to plasma, and, in lung, of Raldh-1 and Raldh-2, which function in RA production. Our results define retinoid homeostatic gene expression from neonatal and adult age and show that while supplementation with VARA acutely alters retinol content and retinoid homeostatic gene expression in neonatal and adult lung, liver and kidney, VARA supplementation of neonates increased adult-age VA content only in the liver.

Highlights

Vitamin A (VA; retinol) is an essential micronutrient for several biological processes, including vision, embryonic development, cell differentiation, growth and development, and regulation of the immune system
Our study addresses three questions: 1) Is there a natural ontogenic progression of tissue VA and retinoid homeostatic gene expression in the neonates of mothers fed VA-marginal diet, and in adults fed VA-marginal diet from weaning? 2) Does VARA supplementation given periodically during the neonatal period affect the expression of retinoid homeostatic genes, either transiently or in a cumulative manner? 3) Does VARA supplementation of neonates have a long-term consequence on retinoid homeostatic gene expression in adults? Together, our results demonstrate significant developmental changes in the levels of some retinoid homeostatic genes, while not others, and reveal that neonatal VARA supplementation results in both short-term changes, and, for certain genes, a prolonged effect that is evident in the adult animal
Our results indicate that each of the genes examined–Lrat (VA storage in liver and lung), Stimulated by retinoic acid 6 (Stra6) (VA uptake in lung), Rbp4 (VA trafficking from liver to plasma), megalin (VA recycling from plasma), retinaldehyde dehydrogenase (Raldh) -1, -2, and -3 (RA production from retinal), and Cyp26A1/B1 (RA terminal oxidation and degradation)–is expressed throughout the neonatal period

Summary

Introduction

Vitamin A (VA; retinol) is an essential micronutrient for several biological processes, including vision, embryonic development, cell differentiation, growth and development, and regulation of the immune system. RA functions as the most active metabolite of VA by activating nuclear transcription factors that regulate the expression of several genes, including several that are involved in the metabolism of retinol, known as retinoid homeostatic genes. VA deficiency (VAD), which may manifest in clinical deficiency or marginal states of low retinoid status, is a common form of micronutrient malnutrition affecting preschool-age children and pregnant women worldwide [1, 2]. In view of the involvement of VA in a wide variety of physiologic and metabolic systems, newborns and neonates may have a need for a higher rate of retinol oxidation and RA formation to support their rapid growth and the differentiation of tissues. The actual biological requirements for VA in this age group are not known

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