The major objective of this research plan is to understand how exogenous retinoids, principally retinoic acid (RA) and 4-hydroxyphenyl retinamide (4-HPR), influence the hepatic metabolism of retinol. Hepatic retinol may potentially follow three main metabolic pathways: esterification with long-chain fatty acids to form retinyl esters, a reversible storage process; exit from the cell into plasma in association with retinol- binding protein (RBP); or oxidation leading to retinaldehyde and then RA, an irreversible activation or degradative process. The regulatory mechanisms that serve to partition retinol among these different pathways are largely unknown. New information has demonstrated the importance of the cellular retinoid-binding proteins in directing retinoids to specific enzymes. Retinol bound to the cellular retinol-binding protein, GRBP, is available for esterification by the microsomal enzyme lecithin: retinol acyltransferase (LRAT) and has also been shown to be the substrate of a microsomal retinol dehydrogenase. Recently, we have shown that liver LRAT activity is strongly regulated by vitamin A nutritional status. In the proposed research we will address 7 specific aims concerning hepatic retinol metabolism. In particular, we will examine how it is regulated by changes in vitamin A nutritional status and by exogenous retinoids with anti-cancer activity. One such retinoid, 4-HPR, has been shown to inhibit carcinogenesis and to be relatively non-toxic but it causes a marked suppression of plasma retinol and RBP. The mechanism of this decrease is not known. The first R aims examine the regulation of microsomal LRAT while Aims 5 and 6 address the synthesis of RBP and the oxidation of retinol, respectively.
In Aim 1 we will determine which retinoids besides RA can regulate LRAT activity. The goal of Aim 2 is to test the hypothesis that there is competition between LRAT and the RBP secretion pathway for retinol. We will examine whether induction of LRAT by retinoids such as 4-HPR reduces the availability of retinol for secretion on RBP.
In Aim 3 we will determine the cellular distribution of LRAT between parenchymal and nonparenchymal cells.
In Aim 4 we will use the technique of radiation inactivation to explore the properties of LRAT in liver and intestinal microsomes and extracts. The goal of Aim 5, which complements Aim 2, is to determine whether RA or 4-HPR acts as a signal to regulate the transcription or translation of RBP.
In Aim 6, we will test the hypothesis that oxidation of CRBP-bound retinol by microsomal retinol dehydrogenase is increased after treatment with RA or 4-HPR. The proposed research is relevant to understanding the normal feedback regulation of retinol metabolism by endogenously-produced RA as well as the influence of retinoids used in cancer chemoprevention, such as RA and 4-HPR,on the metabolism of retinol and the dietary requirement for vitamin A.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
1R01DK046869-01
Application #
3248220
Study Section
Nutrition Study Section (NTN)
Project Start
1993-08-01
Project End
1994-04-30
Budget Start
1993-08-01
Budget End
1994-04-30
Support Year
1
Fiscal Year
1993
Total Cost
Indirect Cost
Name
Allegheny University of Health Sciences
Department
Type
Schools of Medicine
DUNS #
City
Philadelphia
State
PA
Country
United States
Zip Code
19129
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

Showing the most recent 10 out of 16 publications