REGULATION OF HEPATIC RETINOL METABOLISM

Project: Research project

Description

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.
StatusFinished
Effective start/end date8/1/939/29/01

Funding

  • National Institutes of Health
  • National Institutes of Health
  • National Institutes of Health
  • National Institutes of Health
  • National Institutes of Health: $180,143.00
  • National Institutes of Health
  • National Institutes of Health
  • National Institutes of Health
  • National Institutes of Health

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Vitamin A
Liver
Retinoids
Retinol-Binding Proteins
Tretinoin
Lecithins
Esterification
Nutritional Status
Nutritional Requirements
Chemoprevention
Complementary DNA
Research
Cellular Retinol-Binding Proteins
Retinaldehyde
Liver Extracts
Neoplasms
Enzymes
Secretory Pathway
Hep G2 Cells
Cytoplasmic and Nuclear Receptors