Physiology/pathophysiology of vitamin transport; Molecular mechanisms/regulation and cell biology of nutrient transport processes
Recepient of: National Institutes of Health MERIT Awards (R37 DK 56061) for Consistent and Excellent Contributions to Scientific Knowledge (2009-2019); Senior Research Career Scientist Award-DVA (1996-2022); Horace W. Davenport Distinguished Award, the American Physiological Society-Gastrointestinal and Liver Section for life-long contributions to GI Physiology/Pathophysiology (2012); "Athalie Clarke Achievement Award” for significant contribution to medical/basic science research, the University of California-School of Medicine (2015); Professor " Above-Scale", University of California-School of Medicine (2016); Distinguished Professor, University of California-School of Medicine (2018).
The water-soluble vitamins [thiamin (B1), riboflavin (B2), niacin (B3), pantothenic acid (B5), pyridoxine (B6), biotin (B7), folate (B9) , ascorbate] are essential micro-nutrients for normal cellular functions, growth and development. They are involved in a variety of critical metabolic reactions, and thus, their deficiency/suboptimal levels leads to a variety of clinical abnormalities. Humans (other mammals) cannot synthesize these micro-nutrients endogenously, and thus, must obtain them from exogenous sources (diet and gut microbiota) via intestinal/colonic absorption. In addition, the human body has a limited capacity to store these micro-nutrients, and thus, rely heavily on their efficient absorption. Thus, the intestinal tract plays central role in maintaining and regulating normal body homeostasis of these vitamins. Because of that, and since variety of conditions affect intestinal absorption of these micro-nutrients (e.g., genetic defects in the transport systems involved, intestinal inflammation, chronic exposure to alcohol, certain entero-pathogens, certain medications, etc.), studies that aim at understanding the cellular/molecular aspects of vitamin transport are of significant physiological/patho-physiological/nutritional importance.
Studies in our laboratory over the past thirty five years have characterized many physiological/pathophysiological and cell biological aspects of vitamin transport in the small and large intestine and in other organs of the digestive system. Our studies have covered the whole spectrum of biological complexity from the whole (integrative) animal level, to intact tissues, isolated/cultured cells, sub-cellular organelle/components, to the molecular levels, and have utilized state-of-the-art cell/molecular/imaging approaches as well as appropriate transgenic animal models. Currently our focus is on characterizing transcriptional, post-transcriptional and epigenetic regulation of vitamin transport events, cell biology of the trasnport proteins involved (structure-function activity, involvement of accessary proteins, membrane targeting, intracellualr trafficking), effect of external, environmental factors (e.g. chronic alcohol use, chronic exposure to cigarette smoke, infection with certain entero-pathogenic bacteria), and chronic inflammation on the transport processes.
Representative list out of 252 peer-reviewed manuscripts:
1. Connor M, Blair JA and Said HM. Secondary isotopic effects in studies using radiolabeled folate tracers. Nature 287: 253 255, 1980.
2. McCloud E, Ma TY, Grant KE, Mathis RK and Said HM. L Carnitin uptake by human intestinal epithelial cell line Caco 2: Mechansim and regulation. Gastroenterol 111: 1534 1540, 1996.
3. Nguyen TT, Dyer DL, Dunning DD, Rubin SA and Said HM. Human intestinal folate Transport: Cloning, expression and distribution of complementary RNA. Gastroenterol 112:783 791, 1997.
4. Kumar CK, Moyer MP, Dudeja PK and Said HM. A protein tyrosine kinase regulated, pH dependent carrier mediated uptake system for folate by human normal colonic epithelial cell line NCM 460. J Biol Chem 272: 6226 6231, 1997.
5. Marchant JS, Subramanian VS, Parker I and Said HM. Intracellular trafficking and membrane targeting mechanisms of the human reduced folate carrier in mammalian epithelial cells. J Biol Chem 277: 33325-33333, 2002.
6. Subramanian VS, Marchant JS, Parker I and Said HM. Cell biology of the human thiamine transporter-1 (hTHTR1): intracellular trafficking and membrane targeting. J Biol Chem 278: 3976-3984, 2003.
7. Nabokina SM, Reidling JC and Said HM. Differentiation-dependent up-regulation of intestinal thiamin uptake: cellular and molecular mechanisms. J Biol Chem 280: 32676-32682, 2005.
8. Subramanian VS, Marchant J and Said HM. Targeting and trafficking of the human thiamine transporter-2 (hTHTR2) in epithelial cells. J Biol Chem 281: 5233-5245, 2006.
9. Ashokkumar B, Kumar JS, Hecht GA and Said HM. Enteropathogenic Escherichia coli inhibits intestinal vitamin B1 (thiamin) uptake: Studies with human-derived intestinal epithelial Caco-2 cells. Am J Physiol 297: G825-33, 2009.
10. Reidling JC, Lambrecht N, Kassir M and Said HM. Impaired Intestinal Vitamin B1 (Thiamin) Uptake in Thiamin Transporter-2 Deficient Mice. Gastroenterol 138:1802-1809, 2010.
11. Nabokina SM, Subramanian VS and Said HM. Association of PDZ containing protein PDZD11 with the human sodium-dependent multivitamin transporter hSMVT. Am J Physiol: GI Physiol 300: G561-567, 2010.
12. Subramanian VS, Subramanya SB and Said HM. 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 302: G572-578, 2011.
13. Nabokina SM, Senthilkumar SR and Said HM. Tspan-1 interacts with the thiamine transporter-1 in human intestinal epithelial cells and modulates its stability. Am J Physiol 301: G808-G8013, 2011.
14. Nabokina SM, Subramanian VS and Said HM. Effect of clinical mutations on functionality of the human riboflavin transporter-2 (hRFT-2). Mol Genet Metabol 5: 652-657, 2012.
15. Nabokina SM and Said HM. A high affinity and specific carrier-mediated mechanism for uptake of thiamine pyrophosphate (TPP) by human colonic epithelial cells. Am J Physiol 303: G389-G395, 2012.
16. Biswas A, Senthilkumar SR and Said HM. Effect of chronic alcohol exposure on folate uptake by liver mitochondria. Am J Physiol 302: C203-C209, 2012..
17. Subramanian VS, Subramanya SB, Ghosal A, and Said HM. Chronic alcohol feeding inhibits physiological and molecular parameters of intestinal and renal riboflavin transport. Am J Physiol 305: C539-C546, 2013.
18. Padmanabhan S, Subramanian VS, and Said HM. Effect of the cigarette smoke component, 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK), on Physiological and Molecular Parameters of Thiamin Uptake by Pancreatic Acinar Cells. PLoS One 8: e78853, 2013.
19. Nabokina SV, Subramanian SV, Valle JA, and Said HM. Adaptive regulation of human intestinal thiamin uptake: a role for THTR-2 transcriptional regulation. Am J Physiol 305: G593-G599, 2013.
20. Kumar JS, Subramanian VS, Kapadia R, Kashyap M and Said HM. Mammalian colonocytes possess a carrier-mediated mechanism for uptake of vitamin B3 (niacin): studies utilizing human and mouse colonic preparations. Am J Physiol 305: G207-G213, 2013.
21. Ghosal A, Lambrecht N, Subramanya SB, Kapadia R and Said HM. Conditional knockout of the Slc5a6 gene in mouse intestine impairs biotin absorption. Am J Physiol 304: G64-G71, 2013. THIS PAPER WAS SELECTED AS “EDITOR’S PICK” OF THE MONTH.
22. Ghosal A, Chatterjee N, and Said HM. Enterotoxigenic Escherichia coli infection and intestinal thiamin uptake: studies with intestinal epithelial Caco-2 cells. Am J Physiol 305: C1185 – C1191, 2013.
23. Augagneur Y, Jaubert L, Schiavoni M, Pachikara N, Garg A, Usmani-Brown S, Wesolowski D, Zeller S, Ghosal A, Cornillot E, Said HM, Kumar P, Altman S, Ben Mamoun C. Identification and Functional Analysis of the Primary Pantothenate Transporter, PfPAT, of the Human Malaria Parasite Plasmodium falciparum. J Biol Chem 288: 20558-20567, 2013.
24. Srinivasan P, Subramanian VS, Said HM. Mechanisms involved in the inhibitory effect of chronic alcohol exposure on pancreatic acinar thiamin uptake. Am J Physiol 306:G631-G639, 2014.
25. Nabokina SM, Inoue K, Subramanian VS, Valle JE, Yuasa H, and Said HM. Molecular Identification and Functional Characterization of the Human Colonic Thiamine Pyrophosphate Transporter. J Biol Chem 289:4405-4416, 2014.
26. Sassoon CS, Zhu E, Fang L, Subramanian VS, Said HM. Inhibition of intestinal thiamin transport in rat model of sepsis. Crit Care Med 44:e875-81, 2016.
27. Srinivasan P, Thrower EC, Loganathan G, Balamurugan AN, Subramanian VS, Gorelick FS, and Said HM. Chronic nicotine exposure in vivo and in vitro inhibits vitamin B1 (thiamin) uptake by pancreatic acinar cells. PLoS One 10(12):e0143575, 2015.
28. Srinivasan P, Thrower EC, Gorelick FS and Said HM. The cigarette smoke component 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) Inhibits Pancreatic Acinar Mitochondrial Thiamin Pyrophosphate Uptake: Cellular and Molecular Mechanisms. Am J Physiol 310:G874-83, 2016.
29. Nabokina SM, Mel Ramos B, and Said HM. Mechanism(s) involved in the colon-specific expression of the thiamin pyrophosphate (TPP) transporter. PLoS One. 22;11(2):e0149255, 2016.
30. Subramanian VS, Srinivasan P, and Said HM. Uptake of ascorbic acid by pancreatic acinar cells is negatively impacted by chronic alcohol exposure. Am J Physiol 311: C129-C135, 2016. Selected as one of the best of the American Physiological Society research articles for that month. Also, a press release was written by the American Physiological Society publicizing this work was issued on May 12, 2016 (http://www.the-aps.org/mm/hp/Audiences/Public-Press/2016-24.html) together with an editorial in the same journal (Am J Physiol - Cell Physiol. 2016 Jun15:ajpcell.00149.2016.).
31. Agrawal S, Agrawal A, and Said HM. Biotin deficiency enhances the inflammatory response of human dendritic cells. Am J Physiol 311:C386-91, 2016. Manuscript featured as a APS-Select Article, Sept 2016.
32. Sabui S, Bohl JA, Kapadia R, Cogburn K, Ghosal A, Lambrecht NW, Said HM. Role of the sodium-dependent multivitamin transporter (SMVT) in the maintenance of intestinal mucosal integrity. AM J.Physiol 311:G561-70, 2016. This article was elected as a “Featured Article “by the AJP editorial office, Sept 2016.
33. Lakhan R and Said HM. Lipopolysaccharide (LPS) inhibits colonic biotin uptake via interference with membrane expression of its transporter: A role for casein kinase 2 -mediated pathway. Am J Physiol 312:C376-C384, 2017. (Paper selected as an Editor’s Pick article, 2017).
34. Subramanian VS, Sabui S, Teafatiller T, Bohl JA, and Said HM. 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, 2017. (Selected by the Editor-in Chief as a “Featured Article”).
35. Sabui S Subramanian VS, Kapadia R, and Said HM. Adaptive-regulation of pancreatic acinar mitochondrial thiamin pyrophosphate (MTPP) uptake process: Possible involvement of epigenetic mechanism(s). Am J Physiol: GI and Liver Physiol 313: G448-G455, 2017. [Selected by the Editor-in Chief as a “Featured Article”. Also, an editorial was written on this article (Am J Physiol: GI and Liver Physiol. 2017 Aug 24:ajpgi.00256.2017. doi: 10.1152/ajpgi.00256.2017; PMID: 28838988)].
36. Lakhan R, Subramanian VS, and Said HM. Lakhan R, Subramanian VS, and Said HM. Role of MicroRNA-423-5p in post-transcriptional regulation of the intestinal riboflavin transporter-3 (SLC52A3). Am J Physiol: GI and Liver Physiol 313: G589 - G598, 2017.
37. Anandam K, Srinivasan P, Subramanian VS, and Said HM. Molecular mechanisms involved in the adaptive regulation of colonic thiamin pyrophosphate (TPP) uptake process. Am J Physiol: Cell Physiol 313:C655-C663, 2017.
38. Elahi A, Narasappa N, Agrawal S, Sabui S, Lambrecht N, Agrawal A, and Said HM. Biotin deficiency induces Th1/Th17 mediated pro-inflammatory response in human CD4+T lymphocytes via activation of mTOR signaling pathway. J Immunol 200:2563-2570, 2018. ?
39. Sabui S, Kapadia R, Ghosal A, Schneider M, Lambrecht N, and Said H. Biotin (and pantothenic acid) over-supplementation to conditional SLC5A6 KO mice prevents the development of intestinal mucosal abnormalities and growth defects. Am J Physiol: Cell Physiol 315:C73-C79, 2018.
40. Anandam KY, Alwan OA, Subramanian VS, Srinivasan P, Kapadia R, Said HM. Effect of the pro-inflammatory cytokine TNF-a on intestinal riboflavin uptake: Inhibition mediated via transcriptional mechanism(s). Am J Physiol Cell Physiol 315:C653-C663, 2018.
41. Sabui S, Subramanian VS, Pham Q, and Said HM. Identification of transmembrane protein 237 as a novel interactor with the intestinal riboflavin transporter-3 (RFVT-3): role in functionality and cell biology. Am J Physiol Cell Physiol 316:C805-C814, 2019.
42. Srinivasan P, Anandam SY, Ramesh V, Geltz E, and Said HM. Effect of bacterial flagellin on thiamin uptake by human and mouse pancreatic acinar cells: Inhibition mediated at the level of transcription of THTR-1 and 2. Am J Physiol Gastrointest Liver Physiol 316:G735-G743, 2019.
43. Faletra F, Bottega R, Perrone M, Vecchiato K, Taddio A, Sabui S, Pecile V, and Said HM. Functional analysis of the third identified SLC25A19 mutation causative for the thiamine metabolism dysfunction syndrome 4. J Human Genetics 64:1075-1081, 2019.
44. Srinivasan P, Ramesh V, Wu J, Heskett CW, Chu BD, and Said HM. Pyridoxine and pancreatic acinar cells: transport physiology and effect on gene expression profile. Am J Physiol: Cell Physiol 317(6):C1107-C1114, 2019.
45. Skupsky J, Sabui S, Hwang M, Nakasaki M, Cahalan MD, Said HM. Biotin supplementation ameliorates murine colitis by preventing NF-?B activation. Cell. Molec. Gastroenterol Hepatol. 9:557-567, 2020 . [GI and Hepatology News wrote a commentary article on this work entitled “Biotin may benefit patients with IBD” on this work. April 10, 2020. “https://www.mdedge.com/gihepnews/article/220621/ibd-intestinal-disorders/biotin-may-benefit-patients-ibd”].
46. Anandam KY, Sabui S, Thompson M, Subramanian S and Said HM. Enterohemorrhagic Escherichia coli infection inhibits colonic thiamin pyrophosphate uptake via transcriptional mechanism. PLOS ONE 14(10):e0224234, 2019.
47. Ramamoorthy K, Anandam KY, Yasujima T, Srinivasan P, and Said HM. Post-transcriptional regulation of thiamin transporter-1 (THTR-1) expression by microRNA- 200a-3p in pancreatic acinar cells. Am J Physiol: Gastrointest Liver Physiol. 319(3):G323-G332, 2020.
Representative Invited Reviews and Book Chapters:
1. Said HM. Recent advances in carrier-mediated absorption of water-soluble vitamins. Ann Review Physiol 66: 419-446, 2004.
2. Said HM and Seetharam B. Intestinal absorption of water-soluble vitamins. In: Physiology of the Gastrointestinal Tract. Edited by Leonard R. Johnson, Kim Barrett, Fayez K. Ghishan, Juanita L. Merchand, Hamid M. Said and Jackie D. Wood; 4th Edition, Elsevier Press; San Diego; pp 1791-1826, 2006.
3. Said HM and Mohammed ZM. Intestinal absorption of water-soluble vitamins: an update. Curr Opin Gastroenterol 22(2): 140-146, 2006.
4. Said HM. Intestinal absorption of water-soluble vitamins in health and disease. Biochem J 437: 357-72, 2011.
5. Said HM and Ross C. Riboflavin. In: Modern Nutrition in Health and Disease Modern Nutrition in Health and Disease. ROSS C, Caballero B, Cousins RJ, Tucker KL, Ziegler TR, editors; 11th edition, pp 325-330, 2011.
6. Said HM and Nexo E. Intestinal absorption of water-soluble vitamins. In: Physiology of the Gastrointestinal Tract. Edited by Johnson LR, Ghishan FK, Merchand JL, Said HM and Wood JD; 5th Edition , Elsevier Press; San Diego; pp 1711 – 1756, 2012
7. Said HM. 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, invited review (In press, 2013). THIS REVIEW WAS SELECTED AS “EDITOR’S PICK” OF THE MONTH
8. Said HM and Trebble T. Intestinal digestion and absorption of micronutrients. In: Slesenger and Fordtran Gastrointestinal and Liver Disease; Feldman M, Friedman LS, and Brandt LJ, editors; 10th edition; Elsevier publishing; pp 1765 - 1788, 2015.
9. Said HM. Water-soluble vitamins. World Rev Nutr Diet 111:30-37, 2015.
10. Said HM, Nexo E. Intestinal Absorption of Water-Soluble Vitamins: Cellular and Molecular Mechanisms. In: “Physiology of the Gastrointestinal Tract”; 6th Edition. Said HM, Editor-in-Chief; Associate editors: Johnson LR, Ghishan FK, Kaunitz J, Merchand JL, and Wood JD; Elsevier Press; San Diego, PP 1201-1248, 2018.
1. Physiology of the Gastrointestinal Tract. 4th Edition. Leonard R Johnson, Editor-in-Chief; Associate editors Barrett K, Ghishan FK, Kaunitz JD, Merchand JL, Said HM, and Wood JD; Elsevier Press; San Diego; 2006.
2. Physiology of the Gastrointestinal Tract, 5th Edition. Johnson LR, Editor-in-Chief; Associate editors Ghishan FK, Kaunitz JD, Merchand JL, Said HM and Wood JD, editors; Elsevier Press; San Diego; 2012.
3. Physiology of the Gastrointestinal Tract; 6th Edition. Said HM, Editor-in-Chief; Associate editors: Ghishan FK, Kaunitz JD, Merchand JL, and Wood JD; Elsevier Press; San Diego; 2018.
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AGA, APS, AIN, ASCB
Reviewer for NIH and VA Study Sections; Reviewer for the Austrian Science Foundation, Vienna, Austria; the Medical Research Council, London, UK; and the Research Council of Norway, Oslo, Norway
Cellular and Molecular Biosciences