Retinoic acid and related retinoids are potent hormone-like ligand for two families of ligand-activated nuclear receptors, RAR and RXR. Retinoic acid is synthesized from vitamin A precursors in a variety of cells where it potentially acts in situ to induce gene expression, control growth, and promote normal cellular differentness. These actions make retinoids a great interest in situ chemoprevention of cancer. Despite many advances in retinoid receptor biology, our understanding of the factors that regulate endogenous retinoid concentrations has lagged behind. Understanding the production and catabolism of retinoids is critical to understanding their receptor-mediated actions. The central hypothesis to be tested is that two liver microsomal enzymes - lecithin: retinol acyltransferase, LRAT, and cytochrome P450RA1, or CYP26- serve as key regulators of Retinoic acid biosynthesis and catabolism, respectively. Recently we have cloned LRAT cDNA from rat and mouse liver. Preliminary studies are presented in which LRAT and CYP26 gene expression was strongly regulated in liver, both actually by exogenous retinoids and chronically by dietary vitamin A. To critically test our hypothesis we will conduct 4 specific aims.
In aim 1 we will examine retinoid- and diet- induced differences in LRAT and CYP26 gene expression and retinoid metabolism in intact rats.
In aim 2 we will investigate which liver cell types express LRAT and CYP26 and further test our model of retinoid metabolism in hepatocytes and stellate cells.
In aim 3, we will sequence the homologous cDNA for human liver LRAT and conduct molecular studies of LRAT and CYP26 expression in normal and diseased liver specimens available from the Liver Tissue Procurement and Distribution System (LTPADS).
In aim 4, we will study the 5' regulatory regions of the LRAT and CYP26 genes to determine the molecular basis for their responsiveness to Retinoic acid in liver. By investigating both LRAT and CYP26 simultaneously we expect to obtain novel insights into the molecular and cell-type specific regulation of Retinoic acid biosynthesis and degradation. This information could shed new light on the endogenous factors that control the availability of Retinoic acid in tissues and plasma which, in turn, are likely to affect Retinoic acid's anticarcinogenic potential.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA090214-03
Application #
6650248
Study Section
Nutrition Study Section (NTN)
Program Officer
Malone, Winfred F
Project Start
2001-09-01
Project End
2006-08-31
Budget Start
2003-09-01
Budget End
2004-08-31
Support Year
3
Fiscal Year
2003
Total Cost
$250,417
Indirect Cost
Name
Pennsylvania State University
Department
Nutrition
Type
Schools of Allied Health Profes
DUNS #
003403953
City
University Park
State
PA
Country
United States
Zip Code
16802
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
Chen, Qiuyan; Ross, A Catharine (2012) All-trans-retinoic acid and the glycolipid ?-galactosylceramide combined reduce breast tumor growth and lung metastasis in a 4T1 murine breast tumor model. Nutr Cancer 64:1219-27
Zhang, Yao; Wray, Amanda E; Ross, A Catharine (2012) Perinatal exposure to vitamin A differentially regulates chondrocyte growth and the expression of aggrecan and matrix metalloprotein genes in the femur of neonatal rats. J Nutr 142:649-54
Rosen, Clifford J; Abrams, Steven A; Aloia, John F et al. (2012) IOM committee members respond to Endocrine Society vitamin D guideline. J Clin Endocrinol Metab 97:1146-52
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

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