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The present study was designed to evaluate whether and how glucocorticoids can affect obesity-regulated hepatic ischemia-reperfusion (I/R) injury.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.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 24 h 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.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.