title: Chronic alcohol exposure affects pancreatic acinar mitochondrial thiamin pyrophosphate uptake: studies with mouse 266-6 cell line and primary cells.
abstract: 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).
authors: Department of Medical Research, Veterans Affairs Medical Center, Long Beach, California; and Departments of Medicine and Physiology/Biophysics, University of California, Irvine, California.
authors: Padmanabhan
authors: P
authors: Srinivasan
authors: Department of Medical Research, Veterans Affairs Medical Center, Long Beach, California; and Departments of Medicine and Physiology/Biophysics, University of California, Irvine, California.
authors: Svetlana
authors: S
authors: Nabokina
authors: Department of Medical Research, Veterans Affairs Medical Center, Long Beach, California; and Departments of Medicine and Physiology/Biophysics, University of California, Irvine, California hmsaid@uci.edu.
authors: Hamid M
authors: HM
authors: Said
mesh_terms: D000428:Alcohol Drinking; D000818:Animals; D027321:Anion Transport Proteins / Q000235:genetics / Q000378:metabolism*; D001692:Biological Transport; D045744:Cell Line, Tumor; D042002:Chromatin Assembly and Disassembly; D004195:Disease Models, Animal; D044127:Epigenesis, Genetic; D006657:Histones / Q000378:metabolism; D006801:Humans; D026901:Membrane Transport Proteins / Q000235:genetics; D051379:Mice; D008822:Mice, Transgenic; D008928:Mitochondria / Q000378:metabolism* / Q000473:pathology; D033681:Mitochondrial Membrane Transport Proteins; D024101:Mitochondrial Proteins / Q000235:genetics / Q000378:metabolism*; D046790:Pancreas, Exocrine / Q000378:metabolism* / Q000473:pathology; D019512:Pancreatitis, Alcoholic / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D061251:Primary Cell Culture; D011401:Promoter Regions, Genetic; D013835:Thiamine Pyrophosphate / Q000378:metabolism*; D013997:Time Factors; D014158:Transcription, Genetic
chemical_list: D027321:Anion Transport Proteins; D006657:Histones; D026901:Membrane Transport Proteins; D033681:Mitochondrial Membrane Transport Proteins; D024101:Mitochondrial Proteins; C434255:SLC25A19 protein, human; C515239:Slc25a19 protein, mouse; D013835:Thiamine Pyrophosphate
keywords: chronic alcohol exposure; mitochondria; pancreatic acinar cells; thiamin pyrophosphate; uptake