Regulation Of Early Growth Response Factor-1 (Egr-1) By Bile Acids

Cholestasis is a condition that results when excretion of bile acids from the liver is interrupted. Liver injury occurs in both humans and animals as a result of this disease. Recent studies have shown that inflammation is required for injury during cholestasis. Data from our laboratory has shown that early growth response factor‐1 (Egr‐1) is required for inflammation in vivo during cholestasis, and that Egr‐1 is upregulated in hepatocytes exposed to bile acids in vitro . What remains unknown is the mechanism by which bile acids upregulate Egr‐1. Bile acids modulate gene expression through activation of Farnesoid X Receptor (FXR) or by signaling through the mitogen‐activated protein (Map) kinase cascade. To elucidate the mechanism by which bile acids upregulate Egr‐1, primary mouse hepatocytes were isolated from wild‐type and FXR knockout mice and exposed to either deoxycholic acid (DCA) or chenodeoxycholic acid (CDCA). Egr‐1 mRNA was increased after bile acid treatment, however there was no difference in the level of induction between wild‐type and FXR knockout hepatocytes. Consistent with these in vitro findings, Egr‐1 was upregulated in the liver to a similar extent in wild‐type and FXR knockout mice after bile duct ligation. Next primary mouse hepatocytes were isolated and pretreated with U0126, an inhibitor of MEK‐1, a member of the Map kinase cascade. Pretreatment with UO126 prevented upregulation of Egr‐1 mRNA and protein after DCA and CDCA treatment. Results from this study demonstrate that bile acids upregulate Egr‐1 in hepatocytes via the Map kinase cascade.