Chronic Nicotine Exposure In Vivo and In Vitro Inhibits Vitamin B1 (Thiamin) Uptake by Pancreatic Acinar Cells

Srinivasan, Padmanabhan; Thrower, Edwin C.; Loganathan, Gopalakrishnan; Balamurugan, Appakalai N.; Subramanian, Veedamali S.; Gorelick, Fred S.; Said, Hamid M.

doi:10.1371/journal.pone.0143575

Cited by 12 publications

(18 citation statements)

References 48 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Human primary pancreatic acinar cells (hPAC) were isolated from cadaveric pancreatic tissues of organ donors at Islet Cell Laboratory at the University of Louisville (Louisville, KY), and at City of Hope (Duarte, CA). Briefly, after informed consent had been obtained, pancreata of subjects (25-to 65-yr-old males) were removed from the donors and digested to separate islets from ductal-acinar trees and purified as described previously (36). The resulting acini were transported to the University of California, Irvine (Ͻ48 h after isolation) and cultured in Ham's F-12K growth medium supplemented with the following: 10% FCS, 5% BSA, 10 ng/ml epidermal growth factor, and 0.1 mg/ml soybean trypsin inhibitor, as described by us and others before (31,36).…”

Section: Flagellin Exposure Of Human Pacs and Uptake Studiesmentioning

confidence: 99%

“…Using a variety of physiological, cellular, and molecular approaches (including appropriate knockout and knockdown approaches), we have previously shown that thiamin uptake by mouse and human pancreatic acinar cells is via a specific carrier-mediated process and involves thiamin transporters 1 and 2 (THTR-1 and THTR-2) (38,39). Other studies from our laboratory have examined the effect of chronic exposure of PACS to alcohol and to specific components of cigarette smoke on thiamin uptake and have delineated the cellular/molecular mechanisms involved in the identified effects (34,35,36,39).…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Effect of bacterial flagellin on thiamin uptake by human and mouse pancreatic acinar cells: inhibition mediated at the level of transcription of thiamin transporters 1 and 2

Srinivasan

Anandam

Ramesh

et al. 2019

American Journal of Physiology-Gastrointestinal and Liver Physi

Self Cite

View full text Add to dashboard Cite

Thiamin (vitamin B1) is essential for normal cellular metabolism and function. Pancreatic acinar cells (PACs) obtain thiamin from the circulation via a specific carrier-mediated process that involves the plasma membrane thiamin transporters 1 and 2 (THTR-1 and THTR-2; products of SLC19A2 and SLC19A3 genes, respectively). There is nothing known about the effect of bacterial products/toxins on thiamin uptake by PACs. We addressed this issue in the present investigation by examining the effect of bacterial flagellin on physiological and molecular parameters of thiamin uptake by PACs. We used human primary PACs, mice in vivo, and cultured mouse-derived pancreatic acinar 266-6 cells in our investigation. The results showed that exposure of human primary PACs to flagellin led to a significant inhibition in thiamin uptake; this inhibition was associated with a significant decrease in expression of THTR-1 and -2 at the protein and mRNA levels. These findings were confirmed in mice in vivo as well as in cultured 266-6 cells. Subsequent studies showed that flagellin exposure markedly suppressed the activity of the SLC19A2 and SLC19A3 promoters and that this effect involved the Sp1 regulatory factor. Finally, knocking down Toll-like receptor 5 by use of gene-specific siRNA was found to lead to abrogation in the inhibitory effect of flagellin on PAC thiamin uptake. These results show, for the first time, that exposure of PACs to flagellin negatively impacts the physiological and molecular parameters of thiamin uptake and that this effect is mediated at the level of transcription of the SLC19A2 and SLC19A3 genes. NEW & NOTEWORTHY The present study demonstrates, for the first time, that prolonged exposure of pancreatic acinar cells to flagellin inhibits uptake of vitamin B1, a micronutrient that is essential for energy metabolism and ATP production. This effect is mediated at the level of transcription of the SLC19A2 and SLC19A3 genes and involves the Sp1 transcription factor.

show abstract

Section: Flagellin Exposure Of Human Pacs and Uptake Studiesmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Effect of bacterial flagellin on thiamin uptake by human and mouse pancreatic acinar cells: inhibition mediated at the level of transcription of thiamin transporters 1 and 2

Srinivasan

Anandam

Ramesh

et al. 2019

American Journal of Physiology-Gastrointestinal and Liver Physi

Self Cite

View full text Add to dashboard Cite

show abstract

“…In that context, using chemical inhibitors and mice with genetic deletions, several studies have found that pancreatitis effects of NNK (with acinar cells and in vivo) appear to be mediated by an α-7-nicotinic receptor 37 . A very recent study suggested that one action of NNK in the pancreas was to reduce the activity of plasma-membrane and mitochondrial thiamine transporters 38, 39. This NNK effect was linked to reduced cellular mitochondrial function and adenosine triphosphate depletion.…”

Section: Animal Models Of Clinical Acute Pancreatitismentioning

confidence: 99%

Do Animal Models of Acute Pancreatitis Reproduce Human Disease?

Gorelick

Lerch

2017

Cellular and Molecular Gastroenterology and Hepatology

Self Cite

View full text Add to dashboard Cite

Acute pancreatitis is currently the most common cause of hospital admission among all nonmalignant gastrointestinal diseases. To understand the pathophysiology of the disease and as a potential step toward developing targeted therapies, attempts to induce the disease experimentally began more than 100 years ago. Recent decades have seen progress in developing new experimental pancreatitis models as well as elucidating many underlying cell biological and pathophysiological disease mechanisms. Some models have been developed to reflect specific causes of acute pancreatitis in human beings. However, the paucity of data relating to the molecular mechanisms of human disease, the likelihood that multiple genetic and environmental factors affect the risk of disease development and its severity, and the limited information regarding the natural history of disease in human beings make it difficult to evaluate the value of disease models. Here, we provide an overview of key models and discuss our views on their strengths for characterizing cell biological disease mechanisms or for identifying potential therapeutic targets. We also acknowledge their limitations.

show abstract

“…Another possible downstream pathway that has been investigated is thiamine (vitamin B 1 ) uptake by pancreatic acinar cells [ 42 – 44 ]. NKK has been shown to inhibit thiamine uptake in pancreatic acinar cells [ 42 ].…”

Section: Discussionmentioning

confidence: 99%

Cigarette toxin 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) induces experimental pancreatitis through α7 nicotinic acetylcholine receptors (nAChRs) in mice

et al. 2018

View full text Add to dashboard Cite

Clinical studies have shown that cigarette smoking is a dose-dependent and independent risk factor for acute pancreatitis. Cigarette smoke contains nicotine which can be converted to the potent receptor ligand and toxin, NNK [4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone]. Previously, we have shown that NNK induces premature activation of pancreatic zymogens in rats, an initiating event in pancreatitis, and this activation is prevented by pharmacologic inhibition of nicotinic acetylcholine receptors (nAChR). In this study, we determined whether NNK mediates pancreatitis through the α7 isoform of nAChR using α7nAChR knockout mice. PCR analysis confirmed expression of non-neuronal α7nAChR in C57BL/6 (WT) mouse and human acinar cells. NNK treatment stimulated trypsinogen activation in acini from WT but not α7nAChR-/- mice. NNK also stimulated trypsinogen activation in human acini. To further confirm these findings, WT and α7nAChR-/- mice were treated with NNK in vivo and markers of pancreatitis were measured. As observed in acini NNK treatment induced trypsinogen activation in WT but not α7nAChR-/- mice. NNK also induced other markers of pancreatitis including pancreatic edema, vacuolization and pyknotic nuclei in WT but not α7nAChR-/- animals. NNK treatment led to increased neutrophil infiltration, a marker of inflammation, in WT mice and to a significantly lesser extent in α7nAChR-/- mice. We also examined downstream targets of α7nAChR activation and found that calcium and PKC activation are involved down stream of NNK stimulation of α7nAChR. In this study we used genetic deletion of the α7nAChR to confirm our previous inhibitor studies that demonstrated NNK stimulates pancreatitis by activating this receptor. Lastly, we demonstrate that NNK can also stimulate zymogen activation in human acinar cells and thus may play a role in human disease.

show abstract

Chronic Nicotine Exposure In Vivo and In Vitro Inhibits Vitamin B1 (Thiamin) Uptake by Pancreatic Acinar Cells

Cited by 12 publications

References 48 publications

Effect of bacterial flagellin on thiamin uptake by human and mouse pancreatic acinar cells: inhibition mediated at the level of transcription of thiamin transporters 1 and 2

Effect of bacterial flagellin on thiamin uptake by human and mouse pancreatic acinar cells: inhibition mediated at the level of transcription of thiamin transporters 1 and 2

Do Animal Models of Acute Pancreatitis Reproduce Human Disease?

Cigarette toxin 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) induces experimental pancreatitis through α7 nicotinic acetylcholine receptors (nAChRs) in mice

Contact Info

Product

Resources

About