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 intestinal 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.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Research Project (R01)
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Maruvada, Padma
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University of California Irvine
Internal Medicine/Medicine
Schools of Medicine
United States
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Anandam, Kasin Yadunandam; Alwan, Omar A; Subramanian, Veedamali S et al. (2018) Effect of the pro-inflammatory cytokine TNF-? on intestinal riboflavin uptake: Inhibition mediated via transcriptional mechanism(s). Am J Physiol Cell Physiol :
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
Subramanian, Veedamali S; Sabui, Subrata; Subramenium, Ganapathy A et al. (2018) Tumor necrosis factor alpha reduces intestinal vitamin C uptake: a role for NF-?B-mediated signaling. Am J Physiol Gastrointest Liver Physiol 315:G241-G248
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
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
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
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

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