This application focuses on the regulation of retinol esterification by LRAT, a microsomal enzyme that specifically recognize retinol bound to CRBP. Prior work from this group has shown that hepatic LRAT activity is highly sensitive to vitamin A nutritional status and is regulated rapidly by the endogenous retinoid hormone, retinoic acid (RA) and well as by exogenous, synthetic retinoids such as 4-(N-hydroxyphenyl) retinamide (4-HPR). The applicant proposes a cell biological approach to better understand 1) the roles of CRBP in retinol esterification by LRAT, and 2) the regulation of LRAT activity by endogenous and exogenous retinoids. The applicant hypothesizes that the regulation of LRAT activity may be important in regulating the availability of retinol for oxidation.
Specific aims 1 and 2 make use of liver cell lines (HepG2 cells stably transfected with cDNA or anti-sense cDNA and newly cloned cells with features of liver stellate cells) to test the hypothesis that CRBP regulates retinol uptake, esterification, oxidation, metabolite formation, and the secretion of RBP.
In aim 3 the applicant will test the hypothesis that the nuclear retinoid receptor RAR-alpha is a key regulator of endogenous LRAT activity by transfecting cells with a dominant negative mutant of RAR-alpha.
In aim 4, the applicant proposes to clone, characterize and express LRAT activity. It is anticipated that the proposed research will improve the understanding of the normal feedback regulation of retinol metabolism by endogenously-produced RA as well as the influence of therapeutic retinoids used in cancer chemoprevention on the metabolism of retinol and the requirement for dietary vitamin A.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
2R01DK046869-06
Application #
2395894
Study Section
Nutrition Study Section (NTN)
Project Start
1993-08-01
Project End
2001-09-29
Budget Start
1997-09-30
Budget End
1998-09-29
Support Year
6
Fiscal Year
1997
Total Cost
Indirect Cost
Name
Pennsylvania State University
Department
Nutrition
Type
Other Domestic Higher Education
DUNS #
City
University Park
State
PA
Country
United States
Zip Code
16802
Ross, A Catharine; Zolfaghari, Reza (2004) Regulation of hepatic retinol metabolism: perspectives from studies on vitamin A status. J Nutr 134:269S-275S
Ross, A Catharine (2003) Retinoid production and catabolism: role of diet in regulating retinol esterification and retinoic Acid oxidation. J Nutr 133:291S-296S
Hoegberg, Pi; Schmidt, Carsten K; Nau, Heinz et al. (2003) 2,3,7,8-tetrachlorodibenzo-p-dioxin induces lecithin: retinol acyltransferase transcription in the rat kidney. Chem Biol Interact 145:1-16
Zolfaghari, Reza; Ross, A Catharine (2003) Recent advances in molecular cloning of fatty acid desaturase genes and the regulation of their expression by dietary vitamin A and retinoic acid. Prostaglandins Leukot Essent Fatty Acids 68:171-9
Wang, Yuanping; Zolfaghari, Reza; Ross, A Catharine (2002) Cloning of rat cytochrome P450RAI (CYP26) cDNA and regulation of its gene expression by all-trans-retinoic acid in vivo. Arch Biochem Biophys 401:235-43
Zolfaghari, R; Ross, A C (2000) Lecithin:retinol acyltransferase from mouse and rat liver. CDNA cloning and liver-specific regulation by dietary vitamin a and retinoic acid. J Lipid Res 41:2024-34
Yamamoto, Y; Zolfaghari, R; Ross, A C (2000) Regulation of CYP26 (cytochrome P450RAI) mRNA expression and retinoic acid metabolism by retinoids and dietary vitamin A in liver of mice and rats. FASEB J 14:2119-27
Rosales, F J; Ross, A C (1998) A low molar ratio of retinol binding protein to transthyretin indicates vitamin A deficiency during inflammation: studies in rats and a posterior analysis of vitamin A-supplemented children with measles. J Nutr 128:1681-7
Rosales, F J; Ross, A C (1998) Acute inflammation induces hyporetinemia and modifies the plasma and tissue response to vitamin A supplementation in marginally vitamin A-deficient rats. J Nutr 128:960-6
Matsuura, T; Gad, M Z; Harrison, E H et al. (1997) Lecithin:retinol acyltransferase and retinyl ester hydrolase activities are differentially regulated by retinoids and have distinct distributions between hepatocyte and nonparenchymal cell fractions of rat liver. J Nutr 127:218-24

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