Vitamin C is an indispensable micronutrient for normal human health and well-being. Vitamin C deficiency leads to a variety of clinical abnormalities. The vitamin acts as a potent antioxidant and a cofactor for several enzymes, with low intracellular levels causing oxidative stress, a driver for many human diseases. Therefore, studies designed to optimize overall vitamin C body homeostasis are important. Humans have lost the ability to synthesis vitamin C endogenously, and must obtain it via intestinal absorption. The intestinal absorption process involves the human sodium-dependent vitamin C transporters-1 & 2 (hSVCT1& hSVCT2), where hSVCT1 is exclusively expressed at the apical membrane of the polarized enterocytes whereas hSVCT2 is localized basolaterally. The objectives of this proposal are to continue our investigations into the molecular physiology/cell biology of intestina vitamin C uptake process, and to address specific aspects of its pathophysiology as well as to determine the effect of external/internal factors on the uptake process. Our new preliminary studies suggest the involvement of microRNA and epigenetic mechanism(s) in the regulation of hSVCT1 expression, identified putative novel hSVCT1 interacting partners, and show a significant inhibition in vitamin C uptake upon exposure to specific enteric pathogens (EPEC and ETEC), pro-inflammatory cytokines, and to bacterial LPS. Based on these findings, our working hypotheses are: i) microRNA and epigenetic mechanism(s) regulate SVCT1 expression and function; ii) hSVCT1 has interacting partners that affect its physiology/cell biology; and iii) exposure to enteric pathogens, pro- inflammatory cytokines, and to bacterial LPS leads to a significant inhibition in intestinal vitamin C uptake.
Three specific aims are proposed to test these hypotheses and will utilize state-of- the-art cell/molecular approaches. Results of these investigations should provide valuable information regarding the intestinal vitamin C absorption process under normal physiological conditions, and how this event is affected by specific pathophysiological factors. This should ultimately help us in designing effective strategies to optimize normal vitamin C body homeostasis, especially in conditions of deficiency/sub-optimal levels.

Public Health Relevance

Vitamin C is essential for human well-being and must be obtained from the diet via intestinal absorption. The objectives of the studies proposed in this application are to gain further insight into the physiology and pathophysiology of the intestinal absorption process of this essential micronutrient with the ultimate goal to design effective ways to optimize its level in the human body.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
1R01DK107474-01
Application #
9001130
Study Section
Special Emphasis Panel (ZRG1-DKUS-P (06))
Program Officer
Maruvada, Padma
Project Start
2015-12-22
Project End
2020-11-30
Budget Start
2015-12-22
Budget End
2016-11-30
Support Year
1
Fiscal Year
2016
Total Cost
$307,312
Indirect Cost
$56,212
Name
Southern California Institute for Research/Education
Department
Type
DUNS #
622027209
City
Long Beach
State
CA
Country
United States
Zip Code
90822
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
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
Subramanian, Veedamali S; Constantinescu, Alexandru R; Benke, Paul J et al. (2017) Mutations in SLC5A6 associated with brain, immune, bone, and intestinal dysfunction in a young child. Hum Genet 136:253-261
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
Subramanian, Veedamali S; Srinivasan, Padmanabhan; Said, Hamid M (2016) Uptake of ascorbic acid by pancreatic acinar cells is negatively impacted by chronic alcohol exposure. Am J Physiol Cell Physiol 311:C129-35
Udhayabanu, Tamilarasan; Subramanian, Veedamali S; Teafatiller, Trevor et al. (2016) SLC52A2 [p.P141T] and SLC52A3 [p.N21S] causing Brown-Vialetto-Van Laere Syndrome in an Indian patient: First genetically proven case with mutations in two riboflavin transporters. Clin Chim Acta 462:210-214
Sabui, Subrata; Subramanian, Veedamali S; Kapadia, Rubina et al. (2016) Structure-function characterization of the human mitochondrial thiamin pyrophosphate transporter (hMTPPT; SLC25A19): Important roles for Ile(33), Ser(34), Asp(37), His(137) and Lys(291). Biochim Biophys Acta 1858:1883-90