Cystathionine β-synthase is inhibited by epinephrine and norepinephrine over-secretion via NF-κB activation in stress-induced hyperhomocysteinemia

Abstract Stress can elevate plasma homocysteine (Hcy) levels, a key factor in the development of various diseases, leading to hyperhomocysteinemia (HHcy). The enzyme Cystathionine β-synthase (CBS) functions in the trans-sulfuration pathway, which links the methionine cycle to glutathione synthesis. This pathway is essential for the metabolism of homocysteine. However, the precise mechanism by which stress regulates hepatic CBS expression remains unclear. The present study aimed to elucidate the molecular mechanism by which CBS expression is regulated in the livers of restraint-stressed rats. Our results showed that stress-induced over-secretion of epinephrine and norepinephrine (E/NE) activated the β-adrenergic receptor, leading to elevated serum IL-6 levels. Treatment of rat primary hepatocytes with IL-6 for 1 h suppressed both CBS activity and Cbs mRNA expression, concomitant with an enhancement of Sp3-mediated transcriptional repression. Furthermore, we found that IL-6 activates NF-κB via the tyrosine phosphorylation pathway, which in turn potentiates Sp3-mediated repression of Cbs transcription. These findings suggest that E/NE contributes to stress-induced HHcy by inhibiting Cbs transcription through the upregulation of Sp3, and that the IL-6/NF-κB axis plays a critical role in the dysregulation of Hcy metabolism.