Vitamin A, its metabolites and synthetic analogs (collectively known as retinoids) are essential for normal human development and human health. Most of the actions of retinol are mediated by its metabolite retinoic acid, which is synthesized intracellularly from retinol. Therefore, it is essential that a steady state of retinol be provided locally at the site of synthesis. Retinol has very limited solubility in the cells and must be bound by cytosolic proteins in order to facilitate retinol metabolism by enzymes involved in retinoic acid or retinyl ester production, thereby preventing its unspecific oxidation/isomerization. Two known cellular retinol-binding proteins, type I (CRBP-I) and type II (CRBP-II) have been described that bind retinol intracellularly and shown to be essential for retinoid homeostasis in liver, testis, kidney, lung, eye and intestine. We have cloned and characterized a third CRBP, CRBP-III. It specifically binds retinols and is expressed at high levels in heart, muscle, adipose and mammary gland. The central hypothesis of this proposal is that CRBP-III plays a major role in maintaining retinoid homeostasis in these specific tissues. To understand CRBP-III's function in retinoid physiology we have generated a mouse lacking the CRBP-III gene (CRBP-III-/-). The CRBP-III-/- mice appear healthy and viable.
Three specific aims are proposed to enhance our understanding of retinoid physiology in heart, muscle and mammary tissue. First, to evaluate the steady state retinoid levels in tissues normally expressing CRBP-III and its role in postprandial retinoid metabolism in the CRBP-III knockout mouse model.
The second aim will address the hypothesis that CRBP-III can prevent abnormalities during embryogenesis and in adult tissues during dietary vitamin A deficiency by maintaining cellular retinol levels. This will lend understanding to what effect the absence of CRBP-III has on retinoid homeostasis and subsequently organ development and maintenance.
The third aim proposes to study the physiological role of CRBP-III in retinoid metabolism in the mammary gland.
This aim will utilize the CRBP-III-/- mice to test the role of CRBP-III in lactation and in supplying sufficient retinoids in the milk. In addition, the role of CRBP-III in the normal differentiation process of the mammary gland will be investigated using the CRBP-III-/- mice. ? ?
|Zizola, C F; Frey, S K; Jitngarmkusol, S et al. (2010) Cellular retinol-binding protein type I (CRBP-I) regulates adipogenesis. Mol Cell Biol 30:3412-20|
|Zizola, Cynthia F; Schwartz, Gary J; Vogel, Silke (2008) Cellular retinol-binding protein type III is a PPARgamma target gene and plays a role in lipid metabolism. Am J Physiol Endocrinol Metab 295:E1358-68|
|Piantedosi, Roseann; Ghyselinck, Norbert; Blaner, William S et al. (2005) Cellular retinol-binding protein type III is needed for retinoid incorporation into milk. J Biol Chem 280:24286-92|