scholarly journals Effect of chronic alcohol exposure on gut vitamin B7 uptake: Involvement of epigenetic mechanisms and effect of alcohol metabolites

2021 ◽  
Author(s):  
Kalidas Ramamoorthy ◽  
Subrata Sabui ◽  
Padmanabhan Srinivasan ◽  
Saleh Al-Juburi ◽  
Quang Pham ◽  
...  
Keyword(s):  
Gut Microbiota ◽  
Ethyl Oleate ◽  
Alcohol Exposure ◽  
Chronic Alcoholism ◽  
Inhibitory Effect ◽  
Epigenetic Mechanisms ◽  
Epigenetic Alterations ◽  
Chronic Alcohol ◽  
Ethyl Palmitate ◽  
Chronic Alcohol Exposure

Vitamin B7 (biotin) is essential from normal health and its deficiency/sub-optimal levels occur in a variety of conditions including chronic alcoholism. Mammals, including humans, obtain biotin from diet and gut-microbiota via absorption along the intestinal tract. The absorption process is carrier-mediated and involves the sodium-dependent multivitamin transporter (SMVT; SLC5A6). We have previously shown that chronic alcohol exposure significantly inhibits intestinal/colonic biotin uptake via suppression of Slc5a6 transcription in animal and cell line models.. However, little is known about the transcriptional/epigenetic factors that mediate this suppression. Additionally, the effect of alcohol metabolites (generated via alcohol metabolism by gut microbiota and host tissues) on biotin uptake is still unknown. In order to address these questions, we first demonstrated that chronic alcohol exposure inhibits small intestinal and colonic biotin uptake and SMVT expression in human differentiated enteroid and colonoid monolayers. We then showed that chronic alcohol exposures of both, Caco-2 cells and mice, are associated with a significant suppression in expression of the nuclear factor KLF-4 (needed for Slc5a6 promoter activity), as well as with epigenetic alterations (histone modifications). We also found that chronic exposure of NCM460 human colonic epithelial cells as well as human differentiated colonoid monolayers, to alcohol metabolites (acetaldehyde, ethyl palmitate, ethyl oleate) significantly inhibited biotin uptake and SMVT expression. These findings shed light onto the molecular/epigenetic mechanisms that mediate the inhibitory effect of chronic alcohol exposure on intestinal biotin uptake. They further show that alcohol metabolites are also capable of inhibiting biotin uptake in the gut.

Chronic alcohol exposure induced gut microbiota dysbiosis and its correlations with neuropsychic behaviors and brain BDNF/Gabra1 changes in mice

BioFactors ◽  
2018 ◽  
Vol 45 (2) ◽  
pp. 187-199 ◽  
Author(s):  
Zheng Xu ◽  
Can Wang ◽  
Xiaoguang Dong ◽  
Tao Hu ◽  
Lingling Wang ◽  
...  
Keyword(s):  
Gut Microbiota ◽  
Alcohol Exposure ◽  
Chronic Alcohol ◽  
Chronic Alcohol Exposure ◽  
Gut Microbiota Dysbiosis

scholarly journals Chronic alcohol exposure affects pancreatic acinar mitochondrial thiamin pyrophosphate uptake: studies with mouse 266-6 cell line and primary cells

2015 ◽  
Vol 309 (9) ◽  
pp. G750-G758 ◽  
Author(s):  
Padmanabhan Srinivasan ◽  
Svetlana Nabokina ◽  
Hamid M. Said
Keyword(s):  
Cell Line ◽  
Mammalian Cells ◽  
Alcohol Exposure ◽  
Significant Inhibition ◽  
Epigenetic Mechanism ◽  
Pancreatic Acinar Cells ◽  
Chronic Alcohol ◽  
Ethyl Palmitate ◽  
Chronic Alcohol Exposure ◽  
Thiamin Pyrophosphate

Thiamin is essential for normal metabolic activity of all mammalian cells, including those of the pancreas. Cells obtain thiamin from their surroundings and enzymatically convert it into thiamin pyrophosphate (TPP) in the cytoplasm; TPP is then taken up by mitochondria via a specific carrier the mitochondrial TPP transporter (MTPPT; product of the SLC25A19 gene). Chronic alcohol exposure negatively impacts the health of pancreatic acinar cells (PAC), but its effect on physiological/molecular parameters of MTPPT is not known. We addressed this issue using mouse pancreatic acinar tumor cell line 266-6 and primary PAC of wild-type and transgenic mice carrying the SLC25A19 promoter that were fed alcohol chronically. Chronic alcohol exposure of 266-6 cells (but not to its nonoxidative metabolites ethyl palmitate and ethyl oleate) led to a significant inhibition in mitochondrial TPP uptake, which was associated with a decreased expression of MTPPT protein, mRNA, and activity of the SLC25A19 promoter. Similarly, chronic alcohol feeding of mice led to a significant inhibition in expression of MTPPT protein, mRNA, heterogeneous nuclear RNA, as well as in activity of SLC25A19 promoter in PAC. While chronic alcohol exposure did not affect DNA methylation of the Slc25a19 promoter, a significant decrease in histone H3 euchromatin markers and an increase in H3 heterochromatin marker were observed. These findings show, for the first time, that chronic alcohol exposure negatively impacts pancreatic MTPPT, and that this effect is exerted, at least in part, at the level of Slc25a19 transcription and appears to involve epigenetic mechanism(s).

scholarly journals Mechanisms involved in the inhibitory effect of chronic alcohol exposure on pancreatic acinar thiamin uptake

2014 ◽  
Vol 306 (7) ◽  
pp. G631-G639 ◽  
Author(s):  
Padmanabhan Srinivasan ◽  
Veedamali S. Subramanian ◽  
Hamid M. Said
Keyword(s):  
Molecular Mechanisms ◽  
Alcohol Exposure ◽  
Regulatory Elements ◽  
Inhibitory Effect ◽  
Pancreatic Acinar Cells ◽  
Chronic Alcohol ◽  
Sp1 Transcription Factor ◽  
Chronic Alcohol Exposure

Pancreatic acinar cells (PAC) obtain thiamin from the circulation via a carrier-mediated process that involves thiamin transporters 1 and 2 (THTR-1 and THTR-2; products of SLC19A2 and SLC19A3, respectively). Chronic alcohol exposure of PAC inhibits thiamin uptake, and, on the basis of in vitro studies, this inhibition appears to be transcriptionally mediated. The aim of this study was to confirm the involvement of a transcriptional mechanism in mediating the chronic alcohol effect in in vivo settings and to delineate the molecular mechanisms involved. Using transgenic mice carrying full-length SLC19A2 and SLC19A3 promoters, we found that chronic alcohol feeding led to a significant reduction in the activity of SLC19A2 and SLC19A3 promoters (as well as in thiamin uptake and expression of THTR-1 and -2). Similar findings were seen in 266-6 cells chronically exposed to alcohol in vitro. In the latter studies, the alcohol inhibitory effect was found to be mediated via the minimal SLC19A2 and SLC19A3 promoters and involved the cis-regulatory elements stimulating protein 1 (SP1)/gut-enriched Kruppel-like factor and SP1-GG-box and SP1/GC, respectively. Chronic alcohol exposure of PAC also led to a significant reduction in the expression of the SP1 transcription factor, which upon correction (via expression) led to the prevention of alcohol inhibitory effects on not only the activity of SLC19A2 and SLC19A3 promoters but also on the expression of THTR-1 and -2 mRNA and thiamin uptake. These results demonstrate that the inhibitory effect of chronic alcohol exposure on physiological/molecular parameters of thiamin uptake by PAC is mediated via specific cis-regulatory elements in SLC19A2 and SLC19A3 minimal promoters.

CB1R Promotes Chronic Alcohol-Induced Neuronal Necroptosis in Mice Prefrontal Cortex

2020 ◽  
Author(s):  
Lin Ye ◽  
Shuhao Li ◽  
Xiaochen Liu ◽  
Dingang Zhang ◽  
Liliang Li ◽  
...  
Keyword(s):  
Prefrontal Cortex ◽  
Protein Level ◽  
Cannabinoid Receptors ◽  
Alcohol Exposure ◽  
Global Burden ◽  
Dependent Manner ◽  
Chronic Alcohol ◽  
Inverse Agonists ◽  
Alcohol Vapor ◽  
Chronic Alcohol Exposure

Abstract Aims Alcohol abuse induces multiple neuropathology and causes global burden to human health. Prefrontal cortex (PFC) is one of the most susceptible regions to alcohol-induced neuropathology. However, precise mechanisms underlying these effects on PFC remain to be elucidated. Herein, we investigated whether RIP1/RIP3/MLKL-mediated necroptosis was involved in the alcohol-induced PFC injury, and explored the effect that cannabinoid receptors (CBRs) exerted on the neurotoxicity of alcohol. Methods In this study, dynamic development of neuronal necroptosis in the PFC region was monitored after 95% (v/v) alcohol vapor administration for 15 and 30 days, respectively. Selective CBRs agonists or inverse agonists were pretreated according to the experimental design. All the PFC tissues were isolated and further examined by biochemical and histopathological analyses. Results It was found that chronic alcohol exposure increased the protein level of MLKL and also the phosphorylated levels of RIP1, RIP3 and MLKL in a time-dependent manner, all of which indicated the activation of necroptosis signaling. Particularly, compared to astrocytes, neurons from the PFC showed more prototypical necrotic morphology in response to alcohol insults. In parallel, an increased protein level of CB1R was also found after 15 and 30 days alcohol exposure. Administration of specific inverse agonists of CB1R (AM251 and AM281), but not its agonists or CB2R modulators, significantly alleviated the RIP1/RIP3/MLKL-mediated neuronal necroptosis. Conclusion We reported the involvement of RIP1/RIP3/MLKL-mediated necroptosis in alcohol-induced PFC neurotoxicity, and identified CB1R as a critical regulator of neuronal necroptosis that enhanced our understanding of alcohol-induced neuropathology in the PFC.

scholarly journals Chronic alcohol exposure inhibits biotin uptake by pancreatic acinar cells: possible involvement of epigenetic mechanisms

2014 ◽  
Vol 307 (9) ◽  
pp. G941-G949 ◽  
Author(s):  
Padmanabhan Srinivasan ◽  
Rubina Kapadia ◽  
Arundhati Biswas ◽  
Hamid M. Said
Keyword(s):  
Transgenic Mice ◽  
Chronic Exposure ◽  
Methylation Status ◽  
Acinar Cells ◽  
Alcohol Exposure ◽  
Significant Inhibition ◽  
Pancreatic Acinar Cells ◽  
Chronic Alcohol ◽  
Wild Type ◽  
Chronic Alcohol Exposure

Chronic exposure to alcohol affects different physiological aspects of pancreatic acinar cells (PAC), but its effect on the uptake process of biotin is not known. We addressed this issue using mouse-derived pancreatic acinar 266-6 cells chronically exposed to alcohol and wild-type and transgenic mice (carrying the human SLC5A6 5′-promoter) fed alcohol chronically. First we established that biotin uptake by PAC is Na+ dependent and carrier mediated and involves sodium-dependent multivitamin transporter (SMVT). Chronic exposure of 266-6 cells to alcohol led to a significant inhibition in biotin uptake, expression of SMVT protein, and mRNA as well as in the activity of the SLC5A6 promoter. Similarly, chronic alcohol feeding of wild-type and transgenic mice carrying the SLC5A6 promoter led to a significant inhibition in biotin uptake by PAC, as well as in the expression of SMVT protein and mRNA and the activity of the SLC5A6 promoters expressed in the transgenic mice. We also found that chronic alcohol feeding of mice is associated with a significant increase in the methylation status of CpG islands predicted to be in the mouse Slc5a6 promoters and a decrease in the level of expression of transcription factor KLF-4, which plays an important role in regulating SLC5A6 promoter activity. These results demonstrate, for the first time, that chronic alcohol exposure negatively impacts biotin uptake in PAC and that this effect is exerted (at least in part) at the level of transcription of the SLC5A6 gene and may involve epigenetic/molecular mechanisms.

EFFECTS OF CHRONIC ALCOHOL EXPOSURE ON GROWTH AND NUTRITION IN RATS

1976 ◽  
Vol 273 (1 Work in Progr) ◽  
pp. 205-211 ◽  
Author(s):  
Jack Wang ◽  
Mark Marvin ◽  
Bruce Abel ◽  
Richard N. Pierson
Keyword(s):  
Alcohol Exposure ◽  
Chronic Alcohol ◽  
Growth And Nutrition ◽  
Chronic Alcohol Exposure
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