The long-term objectives pf this renewal application continue to focus on developing a Comprehensive understanding of the physiology and pathophysiology of the intestinal absorption process of the water-soluble vitamin B1 (thiamine) at the cellular and molecular levels, how the process is regulated, and how it is affected by external factors like chronic alcohol exposure. Thiamine is indispensable for normal human health arid is obtained from exogenous sources via intestinal absorption. Studies during the current funding period have used Slc19a2 -/-and Slc 9a3 -/- knockout mouse models to show that both thiamin transporter 1 & 2 (THTR-1 & 2) are involved in intestinal thiamin absorption; that the intestinal thiamine uptake process is adaptively regulated by extracellular substrate level via transcriptional mechanism involving the transcriptional factor SP1; that tetraspanin-1 (Tspan-1) and transmembrane 4 super-family member 4 (TM4SF4) proteins are interacting partners with intestinal THTR-1 and THTR-2, respectively and that they affect their physiology/cell biology; and that enteropathogenic Escherichia coli and enterotoxigenic E. Coli inhibit intestinal thiamine uptake. Two additional and very relevant studies were also initiated during the current funding period with the first dealing with the identification of existence of a specific and efficient carrier-mediated system for uptake of the microbiota-generated thiamin pyrophosphate (TPP) in the colon (i.e., the SLC44A4 system), and the second is the demonstration that the inhibitory effect of chronic alcohol feeding/exposure on intestinal thiamine uptake is mediated at the level of transcription of theSLC19A2 and SLG19A3: genes. Based on these new findings, our working hypotheses during the next period will be that the SLC44A4 system is a specific and regulated colonic TPP uptake system, and that transcriptional (e. g., epigenetic) mechanisms are involved in mediating the inhibitory effect of chronic alcohol exposure on intestinal thiamin uptake.
Four specific aims are proposed to address these hypotheses, and will utilize state-of-the-art cellular/molecular approaches. Results of these studies should continue to provide novel information regarding the physiology/pathophysiology of the intestinal vitamin B1 absorption process.

Public Health Relevance

Humans cannot synthesize vitamin B1 (thiamin) but obtain it from exogenous sources via intestinal absorption. The aims pf this proposal are focused on delineating how our intestine absorb thiamin, how the process is regulated, and how certain conditions affect the process leading to deficiency. The ultimate goal is to find ways to optimize body thiamin nutrition, especially in conditions of deficiency/suboptimal levels.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Method to Extend Research in Time (MERIT) Award (R37)
Project #
5R37DK056061-19
Application #
9320720
Study Section
Special Emphasis Panel (NSS)
Program Officer
Maruvada, Padma
Project Start
2014-08-01
Project End
2019-07-31
Budget Start
2017-08-01
Budget End
2018-07-31
Support Year
19
Fiscal Year
2017
Total Cost
Indirect Cost
Name
University of California Irvine
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
046705849
City
Irvine
State
CA
Country
United States
Zip Code
92617
Subramanian, Veedamali S; Sabui, Subrata; Moradi, Hamid et al. (2018) Inhibition of intestinal ascorbic acid uptake by lipopolysaccharide is mediated via transcriptional mechanisms. Biochim Biophys Acta Biomembr 1860:556-565
Elahi, Asif; Sabui, Subrata; Narasappa, Nell N et al. (2018) Biotin Deficiency Induces Th1- and Th17-Mediated Proinflammatory Responses in Human CD4+ T Lymphocytes via Activation of the mTOR Signaling Pathway. J Immunol 200:2563-2570
Lakhan, Ram; Said, Hamid M (2017) Lipopolysaccharide inhibits colonic biotin uptake via interference with membrane expression of its transporter: a role for a casein kinase 2-mediated pathway. Am J Physiol Cell Physiol 312:C376-C384
Anandam, Kasin Yadunandam; Srinivasan, Padmanabhan; Subramanian, Veedamali S et al. (2017) Molecular mechanisms involved in the adaptive regulation of the colonic thiamin pyrophosphate uptake process. Am J Physiol Cell Physiol 313:C655-C663
Subramanian, Veedamali S; Sabui, Subrata; Teafatiller, Trevor et al. (2017) Structure/functional aspects of the human riboflavin transporter-3 (SLC52A3): role of the predicted glycosylation and substrate-interacting sites. Am J Physiol Cell Physiol 313:C228-C238
Lakhan, Ram; Subramanian, Veedamali S; Said, Hamid M (2017) Role of MicroRNA-423-5p in posttranscriptional regulation of the intestinal riboflavin transporter-3. Am J Physiol Gastrointest Liver Physiol 313:G589-G598
Subramanian, Veedamali S; Srinivasan, Padmanabhan; Wildman, Alexis J et al. (2017) Molecular mechanism(s) involved in differential expression of vitamin C transporters along the intestinal tract. Am J Physiol Gastrointest Liver Physiol 312:G340-G347
Sabui, Subrata; Subramanian, Veedamali S; Kapadia, Rubina et al. (2017) Adaptive regulation of pancreatic acinar mitochondrial thiamin pyrophosphate uptake process: possible involvement of epigenetic mechanism(s). Am J Physiol Gastrointest Liver Physiol 313:G448-G455
Srinivasan, Padmanabhan; Thrower, Edwin C; Gorelick, Fred S et al. (2016) Inhibition of pancreatic acinar mitochondrial thiamin pyrophosphate uptake by the cigarette smoke component 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone. Am J Physiol Gastrointest Liver Physiol 310:G874-83
Nabokina, Svetlana M; Ramos, Mel Brendan; Said, Hamid M (2016) Mechanism(S) Involved in the Colon-Specific Expression of the Thiamine Pyrophosphate (Tpp) Transporter. PLoS One 11:e0149255

Showing the most recent 10 out of 71 publications