Dissertation/Thesis Abstract

Metabolic and pathological role of retinyl esters: The role of lecithin:retinol acyl transferase, (LRAT)
by O'Byrne, Sheila M., Ph.D., Columbia University, 2008, 189; 3317655
Abstract (Summary)

The enzyme lecithin:retinol acyl transferase (LRAT) catalyses the transfer of a fatty acyl group to retinol forming a retinyl ester, the storage form of vitamin A. LRAT is believed to be the predominant if not the sole enzyme in the body responsible for the physiologic esterification of retinol. I have studied Lrat-deficient (Lrat-/-) mice to gain a better understanding of how these mice take up and store dietary retinoids and to determine whether other enzymes may be responsible for retinol esterification in the body. Although the Lrat-/- mice possess only trace amounts of retinyl esters in liver, lung, and kidney, they possess elevated (by 2-3-fold) concentrations of retinyl esters in adipose tissue compared with wild type mice. These adipose retinyl ester depots are mobilized in times of dietary retinoid insufficiency. In addition to the elevated retinyl esters, I also observed an up-regulation (3-4-fold) in the level of cytosolic retinol-binding protein type III (CRBPIII) in adipose tissue of Lrat-/- mice. Examination by electron microscopy reveals a striking total absence of large lipid-containing droplets that normally store hepatic retinoid within the hepatic stellate cells of Lrat -/- mice, describing for the first time a lipid droplet whose existence depends on the presence of the enzyme LRAT and the synthesis of retinyl esters. Despite the absence of significant retinyl ester stores and stellate cell lipid droplets, the livers of Lrat-/- mice upon histological analysis appear normal and show no histological signs of liver fibrosis.

Loss of retinyl esters has been associated with metaplasia and increased susceptibility to carcinogens. Reduced levels of the LRAT protein have been found in a variety of human primary tumors as well as in cancer cell lines. I investigated the role of LRAT in mammary carcinogenesis by studying the Lrat-/-. My data indicate that these mice are on the brink of vitamin A deficiency due to their reduced retinyl ester stores and I hypothesized that due to this they would be more susceptible to the carcinogen DMBA. Both Lrat-/- mice and normal wild type were treated with the carcinogen DMBA. I saw no differences in the rate of tumor formation, the types of tumor, the number or size of tumors, the types of secondary tumors between the Lrat-/- and the WT mice. My studies lead me to conclude that LRAT protein does not have a causal role in the rate, type or number of tumors formed in DMBA treated mice.

Green et al. estimated that 40-70% of vitamin A delivered to the milk of lactating rats is derived via plasma retinol-binding protein (RBP) with the rest from postprandial intake (J. Nutr. 131: 1279-82, 2001). To explore the role of RBP in this process, I assessed retinoids levels in milk of lactating RBP-/- and wild type mice consuming a chow diet fed ad lib. No significant differences in milk total retinol levels were observed between the RBP-/- and wild type mice. Total retinol levels at different postpartum days for RBP-/- and wild type mice respectively were: days 1-5, 5.7 ± 2.1 μM and 10 ± 5 μM; days 6-14, 14.5 ± 4.3 μM and 9.2 ± 6.6 μM; and day 15 onward, 10.4 ± 4.2 μM and 16 ± 6.4 μM. Overall, no statistically significant differences in milk retinoid levels were observed. Since RBP-/- mice display milk retinoid levels that are the same as wild type mice, when maintained on a retinoid sufficient chow diet, RBP is not required for maintaining delivery of retinoids for milk production suggesting that milk vitamin A can be acquired solely from dietary retinol. (Abstract shortened by UMI.)

Indexing (document details)
Advisor: Blaner, William S.
School: Columbia University
School Location: United States -- New York
Source: DAI-B 69/05, Dissertation Abstracts International
Subjects: Nutrition
Keywords: Lecithin:retinol acyl transferase, Retinol-binding protein, Retinyl esters, Vitamin A
Publication Number: 3317655
ISBN: 9780549657514
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