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 this application are (1) To identify bile acid activated signal transduction pathways within hepatocytes and to determine the mechanisms by which bile acids utilize receptor tyrosine kinases / other receptors in the pathway activation processes; (2) To determine which bile acid activated downstream 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; (3) To determine whether the mechanisms of in vitro regulation of cholesterol and phospholipid homeostasis, specifically the enzyme CYP7a1, also apply in vivo, using JNK1 and JNK2 null mice as well as in the livers of wild type mice infected with recombinant adenoviruses to express dominant negative c-Jun and dominant negative JNK1. In addition, in Aims 2 and 3, efforts will be made to determine if bile acid activated signaling pathways """"""""cross-talk"""""""" with nuclear receptors e.g., farnesoid X receptor, that are also activated by bile acids.
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