Transcriptional and posttranscriptional regulation of beta(2)-adrenergic receptor gene in rat liver during sepsis

Changes in beta(2)-adrenergic receptor (beta(2)-AR) gene expression in the rat liver during different phases of sepsis were studied. Sepsis was induce d by cecal ligation and puncture (CLP). Septic rats exhibit two metabolical ly distinct phases: an initial hyperglycemic (9 h after CLP; early sepsis) followed by a hypoglycemic phase (18 h after CLP; late sepsis). The [H-3]di hydroalprenolol binding studies show that the density of beta(2)-AR was dec reased by 12 and 35% during the early and late phases of sepsis, respective ly. Western blot analyses depict that the beta(2)-AR protein level was redu ced by 37 and 72% during early and late sepsis, respectively. The reverse t ranscription polymerase chain reaction and Southern blot analyses reveal th at the steady-state level of beta(2)-AR mRNA was decreased by 37% during ea rly phase and 77% during late phase of sepsis. Nuclear run-off assays show that the rate of transcription of beta(2)-AR mRNA was reduced by 36% during early sepsis and 64% during late sepsis. The stability assays indicate tha t the half-life of beta(2)-AR mRNA was shortened by 21 and 50% during the e arly and late phases of sepsis, respectively, indicating that the rate of d egradation of beta(2)-AR mRNA was progressively enhanced during sepsis. The se findings demonstrate that the beta(2)-AR gene was underexpressed in the liver during the progression of sepsis, and, furthermore, the underexpressi on of the beta(2)-AR gene was the result of a reduction in the rate of tran scription coupled with an enhancement in the rate of degradation of beta(2) -AR gene transcripts. Thus our findings that the transcriptional and posttr anscriptional regulation of beta(2)-AR gene associated with decreases in be ta(2)-AR number and its protein expression may provide a molecular mechanis tic explanation for the development of hypoglycemia during the late stage o f sepsis.