Effect of chronic alcohol feeding on physiological and molecular parameters of thiamin uptake by pancreatic acinar cells of transgenic reporter mice carrying the human SLC19A2 and SLC19A3 promoters

Abstract

Thiamin is essential for metabolic functions of pancreatic acinar cells. These cells obtain the vitamin from their surrounding via a specific carrier‐mediated process that involves THTR‐1 and THTR‐2 (products of SLC19A2 and SLC19A3 genes, respectively). We have previously shown that chronic alcohol exposure inhibit thiamin uptake by these cells but little is known if the effect is mediated at the transcriptional level of the involved transporters. We addressed this issue using transgenic mice carrying the human SLC19A2 and SLC19A3 promoters and pancreatic acinar 266–6 cells expressing these human promoters. Chronic alcohol feeding (4 weeks) of transgenic mice led to a significant inhibition in carrier‐mediated thiamin uptake, a reduction in level of the expression of endogenous mouse THTR‐1 and THTR‐2 at the protein and mRNA levels, and a significant reduction in activity of SLC19A2 and SLC19A3 promoters. Similar findings were observed in alcohol exposed 266–6 cells. In the latter model, we were also able to determine the alcohol sensitive region within the SLC19A2 and SLC19A3 promoters using a series of truncated promoter constructs. These studies provide clear evidence that the effect of chronic alcohol exposure on pancreatic acinar thiamin uptake is mediated at the level of transcription of SLC19A2 and SLC19A3 genes. [Supported by DVA and NIH grants DK56061 and AA018071].