β-Adrenergic receptor regulates hepatic apolipoprotein A-I gene expression.

BACKGROUND

β-adrenergic receptor (β-AR) was shown to upregulate hepatic apolipoprotein A-I (apoA-I) expression and reverse atherosclerotic plaques in vivo experiments. However, the effect of β-AR on apoA-I expression in vitro is unknown. The specific mechanism underlying β-AR prevention of atherosclerosis is unclear.

OBJECTIVE

The present study was designed to investigate the molecular mechanism of β-AR-mediated regulation of hepatic apoA-I gene expression.

METHODS

HepG2 cells were preincubated with/without a selective protein kinase A inhibitor (H-89) and then treated with a selective β-AR agonist (BRL37344) or antagonist (SR59230A). The hepatic apoA-I expression was detected by reverse transcription real-time quantitative polymerase chain reaction and Western blot analysis. Enzyme-linked immunosorbent assay was used to evaluate the secretion of apoA-I. A recombinant plasmid containing the apoA-I promoter was constructed and transiently transfected into HepG2 cells, and dual-luciferase reporter assays were used to examine the activity of the apoA-I promoter. A chromatin immunoprecipitation polymerase chain reaction assay was used to evaluate binding activities of hepatocyte nuclear factor-4 (HNF-4), HNF-3, and early growth response protein-1.

RESULTS

β-AR activation significantly upregulated apoA-I expression, promoted apoA-I secretion, and enhanced the activities of the apoA-I promoter, HNF-4, and HNF-3 in hepatocytes, whereas early growth response protein-1 was not affected. Moreover, protein kinase A inhibition partially suppressed the activation of the apoA-I promoter, HNF-4, and HNF-3 and almost completely blocked the upregulation of apoA-I expression induced by β-AR.

CONCLUSION

β-AR activation increased the activities of the apoA-I promoter, HNF-4, and HNF-3, which might account for the mechanism of β-AR-mediated upregulation of hepatic apoA-I expression. β-AR might exert an anti-atherosclerotic effect by upregulating hepatic apoA-I expression and promoting the cholesterol reverse transport process.