The long-term objectives of this proposal are to investigate the cellular and molecular mechanisms involved in the transport of the water-soluble vitamin B1 (thiamin) into pancreatic cells and their regulation. We also aim at examining the effect of chronic ethanol consumption on cellular and molecular parameters of pancreatic thiamin uptake process. Thiamin is essential for the function, growth and development of pancreatic cells. Cellular deficiency of thiamin leads to impairments in intracellular energy metabolism, an increase in oxidative stress, and apoptosis. At the level of pancreatic physiology, thiamin deficiency leads to impairment in both exocrine and endocrine functions. Nothing is currently known about the cellular and molecular mechanisms involved in thiamin uptake by pancreatic acinar and beta cells and their regulation, and about the conditions/factors that affect/interfere with these events. In new preliminary studies we obtained evidence to show that thiamin uptake by pancreatic acinar as well as beta cells to involve carrier- mediated process(es) and that both cell types express thiamin transporter-1 &2 (THTR-1 and THTR-2). We propose to continue these investigations to delineate the cellular and molecular mechanisms involved in thiamin uptake by pancreatic acinar and beta cells and their regulation (Sp.
Aims 1 and 2). We will do so using pancreatic cells isolated from wild-type mice, THTR-1- /- and THTR-2 -/- mice, and transgenic mice carrying the human SLC19A2 and SLC19A3 promoters. We will also use cultured mouse pancreatic acinar and beta cells as models. Chronic ethanol consumption is known to exert profound effects on pancreatic physiology and gene expression, and is a leading cause of pancreatitis. Nothing, however, is known about the effect(s) of chronic alcohol consumption on thiamin uptake and metabolism by pancreatic acinar cells. In new preliminary studies we obtained evidence to show that chronic ethanol consumption in mice leads to a marked decrease in THTR-1 and THTR-2 message levels in the pancreas. We propose to continue these investigations and will delineate the functional consequences of these effects and the molecular mechanism(s) involved as well as the effect of chronic alcohol consumption on thiamin metabolism in pancreatic acinar cells (Sp.
Aim 3). Results of these investigations will provide valuable information regarding thiamin physiology and nutrition in pancreatic cells, and on how chronic alcohol consumption affects these parameters. This should ultimately assist in the development of effective strategies to optimize thiamin pancreatic homeostasis, especially in conditions associated with thiamin deficiency and sub-optimal levels. Vitamin B1 (thiamin) is essential for the normal functions, growth and development of the pancreas and its deficiency leads to impairment in both its exocrine and endocrine functions. There is nothing currently known about how pancreatic cells takes up thiamin and what factors/conditions (including chronic alcohol consumption) affect these processes.
Our aims i n this proposal are to address these issues as such investigations will not only provide valuable information regarding thiamin physiology/nutrition of pancreatic cells and how chronic alcohol use adversely affect these parameters, but they may also assist us in the development of effective strategies to optimize thiamin pancreatic levels, especially in conditions associated with thiamin deficiency and sub-optimal levels.

Public Health Relevance

Vitamin B1 (thiamin) is essential for the normal functions, growth and development of the pancreas and its deficiency leads to impairment in both its exocrine and endocrine functions. There is nothing currently known about how pancreatic cells takes up thiamin and what factors/conditions (including chronic alcohol consumption) affect these processes.
Our aims i n this proposal are to address these issues as such investigations will not only provide valuable information regarding thiamin physiology/nutrition of pancreatic cells and how chronic alcohol use adversely affect these parameters, but they may also assist us in the development of effective strategies to optimize thiamin pancreatic levels, especially in conditions associated with thiamin deficiency and sub-optimal levels.

Agency
National Institute of Health (NIH)
Institute
National Institute on Alcohol Abuse and Alcoholism (NIAAA)
Type
Research Project (R01)
Project #
5R01AA018071-04
Application #
8215757
Study Section
Clinical and Integrative Gastrointestinal Pathobiology Study Section (CIGP)
Program Officer
Gao, Peter
Project Start
2009-05-01
Project End
2014-01-31
Budget Start
2012-02-01
Budget End
2013-01-31
Support Year
4
Fiscal Year
2012
Total Cost
$287,475
Indirect Cost
$61,473
Name
Southern California Institute for Research/Education
Department
Type
DUNS #
622027209
City
Long Beach
State
CA
Country
United States
Zip Code
90822
Srinivasan, Padmanabhan; Subramanian, Veedamali S; Said, Hamid M (2014) Mechanisms involved in the inhibitory effect of chronic alcohol exposure on pancreatic acinar thiamin uptake. Am J Physiol Gastrointest Liver Physiol 306:G631-9
Ghosal, Abhisek; Sekar, Thillai V; Said, Hamid M (2014) Biotin uptake by mouse and human pancreatic beta cells/islets: a regulated, lipopolysaccharide-sensitive carrier-mediated process. Am J Physiol Gastrointest Liver Physiol 307:G365-73
Srinivasan, Padmanabhan; Kapadia, Rubina; Biswas, Arundhati et al. (2014) Chronic alcohol exposure inhibits biotin uptake by pancreatic acinar cells: possible involvement of epigenetic mechanisms. Am J Physiol Gastrointest Liver Physiol 307:G941-9
Nabokina, Svetlana M; Subramanian, Veedamali S; Valle, Judith E et al. (2013) Adaptive regulation of human intestinal thiamine uptake by extracellular substrate level: a role for THTR-2 transcriptional regulation. Am J Physiol Gastrointest Liver Physiol 305:G593-9
Biswas, Arundhati; Elmatari, Daniel; Rothman, Jason et al. (2013) Identification and functional characterization of the Caenorhabditis elegans riboflavin transporters rft-1 and rft-2. PLoS One 8:e58190
Nabokina, Svetlana M; Valle, Judith E; Said, Hamid M (2013) Characterization of the human mitochondrial thiamine pyrophosphate transporter SLC25A19 minimal promoter: a role for NF-Y in regulating basal transcription. Gene 528:248-55
Subramanian, Veedamali S; Subramanya, Sandeep B; Ghosal, Abhisek et al. (2013) Chronic alcohol feeding inhibits physiological and molecular parameters of intestinal and renal riboflavin transport. Am J Physiol Cell Physiol 305:C539-46
Said, Hamid M (2013) Recent advances in transport of water-soluble vitamins in organs of the digestive system: a focus on the colon and the pancreas. Am J Physiol Gastrointest Liver Physiol 305:G601-10
Biswas, Arundhati; Senthilkumar, Sundar Rajan; Said, Hamid M (2012) Effect of chronic alcohol exposure on folate uptake by liver mitochondria. Am J Physiol Cell Physiol 302:C203-9
Subramanian, Veedamali S; Subramanya, Sandeep B; Said, Hamid M (2012) Relative contribution of THTR-1 and THTR-2 in thiamin uptake by pancreatic acinar cells: studies utilizing Slc19a2 and Slc19a3 knockout mouse models. Am J Physiol Gastrointest Liver Physiol 302:G572-8

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