Huan-Qiu Liu1, Rui-Jun Li2, Xin Sun3, Ji Li4. 1. Department of Anaesthesiology, The First Hospital of Jilin University, China. 2. Department of Hand Surgery, The First Hospital of Jilin University, China. 3. Department of Neurology, The First Hospital of Jilin University, China. 4. Department of Anaesthesiology, The First Hospital of Jilin University, China. Electronic address: l_ji@yahoo.com.
Abstract
AIMS: The present study was designed to evaluate whether and how glucocorticoids can affect obesity-regulated hepatic ischemia-reperfusion (I/R) injury. MAIN METHODS: To this end, we first examined whether hydrocortisone (HCT) has protective effects on liver damage induced by hepatic I/R injury in mice receiving high fat diet treatment. We then explored the role of GR expression and phosphorylation in the anti-apoptotic effects of hydrocortisone upon hepatic I/R injury. KEY FINDINGS: We found that HCT reduced hepatic necrosis and inflammatory infiltration after hepatic I/R injury in mice that received high fat diet treatment. However, HCT lost the anti-apoptotic effects in high-fat diet treated mice. This phenomenon was associated with increased GRβ expression, decreased basal levels of GR phosphorylation at Ser220 and lack of HCT-induced GR phosphorylation at Ser220 in high-fat diet treated mice. Additionally, basal levels of ERK phosphorylation was increased in high-fat diet treated mice, and I/R injury was associated with robustly increased ERK phosphorylation in high-fat diet treated mice, compared to normal diet treated mice. Furthermore, we demonstrated that high fat diet treated ERK1-/- mice exhibited robustly reduced apoptosis rate at 24h after reperfusion, compared to high fat diet treated wild-type mice. Importantly, there was a decreased level of GRβ after high fat diet treatment in ERK1-/- mice. SIGNIFICANCE: These results together suggested that ERK1 phosphorylation plays a critical role in regulating GRβ expression and HCT-induce GR phosphorylation at Ser220, which is critical for the anti-apoptotic effects HCT on hepatic I/R injury.
AIMS: The present study was designed to evaluate whether and how glucocorticoids can affect obesity-regulated hepatic ischemia-reperfusion (I/R) injury. MAIN METHODS: To this end, we first examined whether hydrocortisone (HCT) has protective effects on liver damage induced by hepatic I/R injury in mice receiving high fat diet treatment. We then explored the role of GR expression and phosphorylation in the anti-apoptotic effects of hydrocortisone upon hepatic I/R injury. KEY FINDINGS: We found that HCT reduced hepatic necrosis and inflammatory infiltration after hepatic I/R injury in mice that received high fat diet treatment. However, HCT lost the anti-apoptotic effects in high-fat diet treated mice. This phenomenon was associated with increased GRβ expression, decreased basal levels of GR phosphorylation at Ser220 and lack of HCT-induced GR phosphorylation at Ser220 in high-fat diet treated mice. Additionally, basal levels of ERK phosphorylation was increased in high-fat diet treated mice, and I/R injury was associated with robustly increased ERK phosphorylation in high-fat diet treated mice, compared to normal diet treated mice. Furthermore, we demonstrated that high fat diet treated ERK1-/- mice exhibited robustly reduced apoptosis rate at 24h after reperfusion, compared to high fat diet treated wild-type mice. Importantly, there was a decreased level of GRβ after high fat diet treatment in ERK1-/- mice. SIGNIFICANCE: These results together suggested that ERK1 phosphorylation plays a critical role in regulating GRβ expression and HCT-induce GR phosphorylation at Ser220, which is critical for the anti-apoptotic effects HCT on hepatic I/R injury.