Diet-derived vitamin A (retinol) is first stored in tissues as retinyl esters (RE), which, through hydrolysis and controlled oxidative metabolism generate bioactive retinoids, including retinoic acid (RA). Retinoic acid is a critical regulator of cell differentiation. For the lungs, RA is crucial for normal postnatal alveolar development and maturation. RA is the only small molecule shown to induce lung alveolar septation (septal outgrowth), which is required for development of full respiratory capacity. RA also has shown therapeutic benefits in models of adult lung emphysematous disease and tissue regeneration after surgery. Our central hypothesis is: A nutrient-metabolite combination , VARA, comprised of vitamin A and its hormone-like metabolite all-trans-RA, will act synergistically to promote RE formation in the lungs of neonates. VARA-induced RE formation may establish conditions beneficial for endogenous production of retinoids, and facilitate alveolar remodeling (septation).
In Aim 1 we will test the hypothesis that VARA synergistically increases RE in the lungs by examining: (1a) the effectiveness of several retinoids to synergize with retinol;(1b) whether the uptake by the lungs of newly absorbed VA contained in chylomicrons is increased in the presence of RA;and (1c) whether inflammation, a concomitant factor in lung immaturity, modifies or attenuates the synergistic response we have observed in the lungs of neonates treated with VARA.
In Aim 2 we will examine functional outcomes of VARA treatment, through studies of time-dependent gene expression and localization of key factors (LRAT, CYP26B1, and DHRS3, a retinal reductase) in the lungs and liver. Finally, in this aim will also test whether VARA improves lung maturation in a clinically relevant model of glucocorticoid-inhibited alveolar septation. These two integrated aims will provide new knowledge regarding the potential of VARA to promote cellular differentiation and organ maturation, and ameliorate impaired postnatal lung development.
The combination of vitamin A and retinoic acid, VARA, through its ability to increase a stable pool of retinyl esters in the lungs, may establish conditions that are conducive to lung maturation and repair. VARA thus appears to have clinical potential for preventing neonatal bronchopulmonary dysplasia, treating lung damage later in life, and, potentially, for cancer chemoprevention. By revealing the molecular effects of vitamin A, RA, and VARA on genes and enzymes in the lungs in an animal model, this research will establish whether VARA warrants further preclinical testing as a therapy for newborns at high risk of chronic lung disease, and for repair of lung injury or chemoprevention in adults.
|Hao, Lei; Huang, Kuan-Hsun; Ito, Kyoko et al. (2016) Fibroblast Growth Factor 21 (Fgf21) Gene Expression Is Elevated in the Liver of Mice Fed a High-Carbohydrate Liquid Diet and Attenuated by a Lipid Emulsion but Is Not Upregulated in the Liver of Mice Fed a High-Fat Obesogenic Diet. J Nutr 146:184-90|
|Zolfaghari, Reza; Ross, A Catharine (2014) Hepatocyte nuclear factor 4? (HNF4?) in coordination with retinoic acid receptors increases all-trans-retinoic acid-dependent CYP26A1 gene expression in HepG2 human hepatocytes. J Cell Biochem 115:1740-51|
|Hao, Lei; Ito, Kyoko; Huang, Kuan-Hsun et al. (2014) Shifts in dietary carbohydrate-lipid exposure regulate expression of the non-alcoholic fatty liver disease-associated gene PNPLA3/adiponutrin in mouse liver and HepG2 human liver cells. Metabolism 63:1352-62|
|Wu, Lili; Ross, A Catharine (2013) Inflammation induced by lipopolysaccharide does not prevent the vitamin A and retinoic acid-induced increase in retinyl ester formation in neonatal rat lungs. Br J Nutr 109:1739-45|
|Restori, Katherine H; Kennett, Mary J; Ross, A Catharine (2013) Immunization with pneumococcal polysaccharide serotype 3 and lipopolysaccharide modulates lung and liver inflammation during a virulent Streptococcus pneumoniae infection in mice. Clin Vaccine Immunol 20:639-50|
|Ito, Kyoko; Hao, Lei; Wray, Amanda E et al. (2013) Lipid emulsion administered intravenously or orally attenuates triglyceride accumulation and expression of inflammatory markers in the liver of nonobese mice fed parenteral nutrition formula. J Nutr 143:253-9|
|Zhang, Y; Chen, Q; Ross, A C (2012) Retinoic acid and tumor necrosis factor-? induced monocytic cell gene expression is regulated in part by induction of transcription factor MafB. Exp Cell Res 318:2407-16|
|Ross, A Catharine (2012) Use of laboratory studies for the design, explanation, and validation of human micronutrient intervention studies. J Nutr 142:157S-60S|
|Tan, Libo; Wray, Amanda E; Ross, A Catharine (2012) Oral vitamin A and retinoic acid supplementation stimulates antibody production and splenic Stra6 expression in tetanus toxoid-immunized mice. J Nutr 142:1590-5|
|Zolfaghari, Reza; Chen, Qiuyan; Ross, A Catharine (2012) DHRS3, a retinal reductase, is differentially regulated by retinoic acid and lipopolysaccharide-induced inflammation in THP-1 cells and rat liver. Am J Physiol Gastrointest Liver Physiol 303:G578-88|
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