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Involvement of transcriptional/epigenetics mechanisms in mediating the inhibitory effect of chronic alcohol exposure, and effect of alcohol metabolites on intestinal uptake of biotin.
Author(s) -
Srinivasan Padmanabhan M.,
Ramamoorthy Kalidas,
Chu Brain D.,
Juburi Saleh A.L.,
Said Hamid M.
Publication year - 2020
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.2020.34.s1.08907
Subject(s) - biotin , dna methylation , epigenetics , biology , biochemistry , vitamin , h3k4me3 , endocrinology , chemistry , gene expression , promoter , gene
Biotin is indispensable for normal cellular metabolism, proliferation and survival. The vitamin acts as a co‐factor for multiple carboxylases that play critical roles in fatty acid, glucose and amino acid metabolism. Emerging evidence has also shown important roles for biotin in immune function and in gene expression, as well as in the maintenance of intestinal integrity and homeostasis. Humans and other mammals cannot synthesize biotin, and thus, must obtain the vitamin from exogenous sources (diet and the gut microbiota) via absorption in the gut. We had previously observed that chronic alcohol feeding/exposure leads to a significant inhibition in small intestinal and colonic biotin uptake ( Am J Physiol Gastrointest Liver Physiol 300: G494–G501, 2011). The aim of this study was to elucidate the role of transcriptional/epigenetic factors in mediating the inhibitory effect of chronic alcohol on intestinal uptake of biotin, and to study the effect of alcohol metabolites on biotin uptake in the large intestine. Our results showed that the inhibition in biotin uptake by intestinal epithelial Caco‐2 cells upon chronic exposure to alcohol is associated with a decrease in the expression of KLF‐4, a key transcription factor involved in the regulation of SLC5A6 . We also observed (using Chip‐qPCR) that exposure of Caco‐2 cells to alcohol to lead to decrease in the euchromatin histone markers (activators‐H3K4me3 and H3K9Ac) and an increase in the heterochromatin histone marker (repressor – H3K27me3) at the SLC5A6 P1 promoter. However, DNA methylation status appeared to be unaltered in these cells upon alcohol exposure. We confirmed the above effects of alcohol on histone modifications in vivo using small intestinal mucosa from mice chronically fed alcohol. We also examined the effect of the alcohol metabolites ethyl oleate (3 mM), ethyl palmitate (3 mM) and acetaldehyde (500 μM) on biotin uptake by human colonic epithelial NCM460 cells and observed a significant inhibition in carrier‐mediated biotin uptake in these cells. Studies are in progress to delineate the exact molecular mechanism(s) involved in this inhibitory effect. This study show, for the first time, that exposure of small intestinal epithelial cells to alcohol alters the epigenetic profile at the SLC5A6 promoters and the expression of an important nuclear factor that drive promoter activity, and that these changes contribute to the inhibition in biotin uptake. Further, the results show that relevant alcohol metabolites inhibit biotin uptake by colonic epithelial cells. Support or Funding Information DVA and the NIH (DK‐56061, DK58057, and AA 018071