Vitamin A derivative all-trans-retinoic acid regulates the expression of over 530 different genes. Consequently, the levels of retinoic acid during embryogenesis are controlled in a spatially and temporally precise manner. However, the molecular mechanisms underlying this regulation are not yet fully understood. The long-term objective of this project is to determine the role of short-chain dehydrogenases/reductases (SDRs) in the regulation of retinoic acid biosynthesis in health and disease. Recently, we have identified a new member of the SDR superfamily of proteins in frogs, rdhe 2, that is highly active as an all-trans-retinol dehydrogenase and is critical for embryonic development in Xenopus laevis. Importantly, there appears to be a functional equivalent of the frog rdhe2 in mammals, which exhibits an all-trans-retinol dehydrogenase activity and is expressed during early embryonic development. We propose that this novel enzyme, named RDH-E2S, is essential for retinoic acid biosynthesis in mammals during embryogenesis and, possibly, in adulthood. To test this hypothesis, we will characterize the catalytic properties of mammalian RDH-E2S and determine its contribution to retinoic acid biosynthesis in vivo using genetically modified mouse model (Specific Aim 1). Our preliminary studies indicate that silencing of retina short-chain dehydrogenase/reductase 1 (retSDR1) gene expression in human cells results in significant increase in the levels of both retinoic acid and retinaldehyde, which translates into dramatic upregulation of retinoic acid-responsive genes. This finding suggests that the rate of retinoic acid biosynthesis is determined by the relative activities of retinol dehydrogenases and retinaldehyde reductases, which together control the levels of retinoic acid precursor, retinaldehyde. To test this hypothesis, we propose to characterize the catalytic properties of retSDR1 and to determine its role in the regulation of retinoic acid levels in vivo using genetically modified mice, human skin organ culture, and Xenopus laevis in vitro model of early embryonic development (Specific Aim 2). These studies will fill the gaps in our understanding of the mechanisms responsible for the maintenance of retinoic acid homeostasis by providing new information regarding the roles of potentially important components of the retinoid regulatory system. The results of these studies will be important for understanding the pathophysiology of disorders associated with disruptions of retinoid homeostasis, such as fetal alcohol syndrome, alcoholic liver disease, carcinogenesis, and diabetes.

Public Health Relevance

All-trans-retinoic acid is the most potent of the biologically active derivatives of vitamin A, which regulates the expression of over 530 different genes. We have identified two members of the short-chain dehydrogenase/reductase superfamily of proteins that may be very important for the biosynthesis and regulation of retinoic acid levels during development as well as adulthood. The results of the proposed studies will provide information important for understanding the pathophysiology of disorders associated with disruptions of retinoid homeostasis, such as fetal alcohol syndrome, alcoholic liver disease, carcinogenesis, and diabetes.

Agency
National Institute of Health (NIH)
Institute
National Institute on Alcohol Abuse and Alcoholism (NIAAA)
Type
Research Project (R01)
Project #
5R01AA012153-12
Application #
8725024
Study Section
Integrative Nutrition and Metabolic Processes Study Section (INMP)
Program Officer
Brooks, Pj
Project Start
2000-04-01
Project End
2018-08-31
Budget Start
2014-09-01
Budget End
2015-08-31
Support Year
12
Fiscal Year
2014
Total Cost
Indirect Cost
Name
University of Alabama Birmingham
Department
Biochemistry
Type
Schools of Medicine
DUNS #
City
Birmingham
State
AL
Country
United States
Zip Code
35294
Wu, Lizhi; Chaudhary, Sandeep C; Atigadda, Venkatram R et al. (2016) Retinoid X Receptor Agonists Upregulate Genes Responsible for the Biosynthesis of All-Trans-Retinoic Acid in Human Epidermis. PLoS One 11:e0153556
Martí-Solans, Josep; Belyaeva, Olga V; Torres-Aguila, Nuria P et al. (2016) Coelimination and Survival in Gene Network Evolution: Dismantling the RA-Signaling in a Chordate. Mol Biol Evol 33:2401-16
Adams, Mark K; Lee, Seung-Ah; Belyaeva, Olga V et al. (2016) Characterization of human short chain dehydrogenase/reductase SDR16C family members related to retinol dehydrogenase 10. Chem Biol Interact :
Atigadda, Venkatram R; Xia, Gang; Deshpande, Anil et al. (2015) Conformationally Defined Rexinoids and Their Efficacy in the Prevention of Mammary Cancers. J Med Chem 58:7763-74
Belyaeva, Olga V; Chang, Chenbei; Berlett, Michael C et al. (2015) Evolutionary origins of retinoid active short-chain dehydrogenases/reductases of SDR16C family. Chem Biol Interact 234:135-43
Adams, Mark K; Belyaeva, Olga V; Wu, Lizhi et al. (2014) The retinaldehyde reductase activity of DHRS3 is reciprocally activated by retinol dehydrogenase 10 to control retinoid homeostasis. J Biol Chem 289:14868-80
Kedishvili, Natalia Y (2013) Enzymology of retinoic acid biosynthesis and degradation. J Lipid Res 54:1744-60
Belyaeva, Olga V; Lee, Seung-Ah; Adams, Mark K et al. (2012) Short chain dehydrogenase/reductase rdhe2 is a novel retinol dehydrogenase essential for frog embryonic development. J Biol Chem 287:9061-71
Lee, Seung-Ah; Belyaeva, Olga V; Wu, Lizhi et al. (2011) Retinol dehydrogenase 10 but not retinol/sterol dehydrogenase(s) regulates the expression of retinoic acid-responsive genes in human transgenic skin raft culture. J Biol Chem 286:13550-60
Lee, Seung-Ah; Belyaeva, Olga V; Kedishvili, Natalia Y (2011) Evidence that proteosome inhibitors and chemical chaperones can rescue the activity of retinol dehydrogenase 12 mutant T49M. Chem Biol Interact 191:55-9

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