Growth-related gene expression in early cholestatic liver injury

Extrahepatic biliary obstruction initiates cholestasis, bile duct proliferation, periportal fibrosis, and, eventually, lethal biliary cirrhosis. Little is known about the genetic regulation of the cellular proliferation and differentiation that begins with the onset of bile duct obstruction. To focus this and future gene expression studies, we sought to determine the time frame for growth-related gene expression and questioned whether the in vivo expression of the protooncogenes H-ras and c-myc was altered after bile duct obstruction.

Female Fisher rats underwent ligation and division of the common bile duct or sham laparotomy.

After obstruction, serum bilirubin and gamma-glutamyl transpeptidase rose to 24% and 30%, respectively, of maximum levels by 10 days after ligation. Morphologic evidence of proliferation of bile duct epithelial cells was first evident after 3 days. After hybridization to c-DNA probes, densitometry for H-ras and beta-actin revealed an immediate and parallel increase in steady-state levels of expression after 24 hours of cholestasis. Levels of c-myc messenger RNA were elevated during the first 3 days of cholestasis; however, at 7 and 10 days c-myc expression was depressed 16% and 60%, respectively.

These profiles of expression show an oncogene response induced by early cholestasis. These data showed that elevations in H-ras and c-myc steady-state expression accompany the proliferative response of bile duct epithelial cells. Decreased levels of c-myc after initial elevation infer that ductal proliferation may continue independently of its steady-state expression, a response usually seen in vitro rather than in in vivo proliferation.