Abstract
Liver alcohol dehydrogenase (ADH) is increased by physiological stress and by chronic administration of growth hormone (GH). Endotoxin plays a role in the pathogenesis of alcoholic liver disease. The effect of lipopolysaccharide (LPS), the endotoxin component of Gram-negative bacteria, was determined on liver ADH. LPS given daily to rats for 3 days increased ADH mRNA, ADH protein, and ADH activity. Nuclear factor-kappaB (NF-kappaB) in the liver nuclear extracts bound to an oligonucleotide specifying region -226 to -194 of the ADH promoter, whereas upstream stimulatory factor (USF) was shown previously to bind to a more proximal site. LPS increased NF-kappaB and USF binding to the ADH promoter. The NF-kappaB (p65) and NF-kappaB (p50) expression vectors inhibited the transfected ADH promoter activity, which contrasts with the previously demonstrated stimulation by an USF expression vector. The binding activities of STAT5b and of C/EBPbeta, which mediate the effect of GH on ADH, were not changed or decreased, respectively, by LPS, indicating that GH plays no intermediary role in the effect of LPS. This study shows that LPS increases ADH and that this effect is mediated by increased binding of USF to the ADH promoter and not by NF-kappaB, which has an inhibitory action.
Highlights
CCAAT/enhancer binding protein , upstream regulatory factor (USF), and signal transduction and activator of transcription 5b (STAT5b) are transcription factors that bind to and activate the alcohol dehydrogenase (ADH) promoter in transfection experiments
This study shows that LPS increases ADH and that this effect is mediated by increased binding of upstream stimulatory factor (USF) to the ADH promoter and not by nuclear factor-B (NF-B), which has an inhibitory action
This study shows that LPS increases the message, protein, and activity of liver ADH
Summary
CCAAT/enhancer binding protein , upstream regulatory factor (USF), and signal transduction and activator of transcription 5b (STAT5b) are transcription factors that bind to and activate the ADH promoter in transfection experiments. C/EBP binds principally between Ϫ22 and Ϫ11 (3), USF between Ϫ60 and Ϫ52 (4), and STAT5b between Ϫ211 and Ϫ203 (5) relative to the start site of transcription. The action of growth hormone (GH) in enhancing the ADH promoter activity is mediated by both C/EBP (6) and STAT5b (5). Endotoxin originating from intestinal bacteria is an important mediator of hepatocellular inflammation in the intragastric-feeding rat model of alcoholic liver disease (7, 8). LPS activates the hypothalamo-hypophyseal-adrenocortical axis, and this is manifested principally by increases in ACTH and cortisol secretion (11). The effect of LPS on GH is species-dependent with increases in the human but decreases in the rat (11). The purpose of the study was to determine whether LPS with its associate acute phase metabolic response influences ADH and whether such an effect on ADH is mediated by NF-B
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