BILE ACID SIGNALING &HEPATIC CHOLESTEROL METABOLISM

Virginia Commonwealth University, Richmond VA

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Abstract

Bile acids may help to coordinately regulate cholesterol and phospholipid metabolism in the hepatocyte by modulating the expression of genes encoding bile acid biosynthetic enzymes and phospholipid transport proteins. The mechanisms by which bile acids coordinate the expression of these genes in order to maintain cholesterol homeostasis and the secretion of a specific ratio of cholesterol: bile acids: phospholipids into bile is unclear, but may have important implications in the pathogenesis of cholesterol gallstone formation, hypercholesterolemia, and cholestatic liver diseases. The objectives of the present grant application are: (1) To identify bile acid-activated signaling cascades within the hepatocyte and determine if the activation occurs via a protein kinase C-dependent or independent pathway; (2) To determine if bile acids activate receptor protein tyrosine kinases (RPTK) in primary hepatocytes and the bile acid structural requirements for activation; (3) To determine which bile acid-activated down-stream signaling cascade(s) regulate genes involved in maintaining cholesterol and phospholipid homeostasis in the hepatocyte, including: CYP7a1, CYP8b1, LDL receptor, neutral cholesterol ester hydrolase (CEH) and mdr2 phospholipid transporter; (4) To determine if the regulation of CYP7a1 by bile acids and cholesterol metabolism is altered in JNK-1 and JNK-2 knock-out mice and if over-expression of a dominant negative JNK-1 or c-Jun alters CYP7a1 regulation by bile acids in bile acid fed rats and in a chronic bile fistula rat model. Efforts will be made to determine if bile acids activated signaling pathways "cross-talk" with nuclear receptors i.e. farnesoid X receptor that are also activated by bile acids.