SIGNAL TRANSDUCTION AND REGULATION BY BILE ACIDS

Virginia Commonwealth University, Richmond VA

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Abstract

DESCRIPTION (Applicant's Abstract): The hepatic biosynthesis of bile acids constitutes a major excretory pathway of cholesterol from the body. Bile acid feedback inhibits the transcriptional activity of the rate-determining enzyme in the neutral bile acid biosynthetic pathway, cholesterol 7alpha-hydroxylase (CYP7A1), as well as the first enzyme in the acidic pathway, sterol 27-hydroxylase (CYP27). Moreover, bile acids up-regulate the activity of mdr2, a transporter of phospholipid into bile. The mechanisms by which bile acids coordinate the expression of these genes remains undefined, but may have important implications in human diseases such as cholesterol gallstone disease and hyperlipidemia, in which bile acids play a pathogenetic role. This research proposal's broad objective is to explore the mechanisms by which bile acids regulate and coordinate cholesterol homeostasis in the hepatocyte by examining two specific aims: 1) to identify the bile acid-activated signal transduction pathways in primary rat hepatocytes, define the bile acid structural characteristics and PKC-dependence requirement for activation of these pathways. To determine which bile acid-induced signaling cascade(s) regulate the expression of CYP7A1 and CYP27 and the mdr2 transporter. 2) To determine the role of receptor and non-receptor tyrosine kinases in bile acid-mediated activation of the signaling cascades. The results of the studies outlined in this proposal will greatly improve our understanding of the role of bile acids in regulating cholesterol metabolism in the liver.