In this investigation we propose to elucidate the relationship between inherited defects of bile acid synthesis and the development of clinical syndromes. We shall: (a) describe the clinical and morphologic features that arise from a defect in bile acid formation; (b) identify bile alcohols that accumulate proximal to the block in the pathway and determine whether cholic acid, chenodeoxycholic acid or both synthetic pathways are affected; (c) define the inherited enzymatic abnormality, and (d) test the effect of administered bile acid on feedback inhibition of the abnormal pathway with the goal of restoring normal hepatic function and reversing the clinical problems. An important goal of this program will be the detailed investigation of the normal synthetic pathways for both cholic acid and chenodeoxycholic acid and to determine the relationship between bile acid feeding and levels of circulating lipoproteins. An additional goal will be the elucidation of factors which regulate cholesterol 7-alpha-hydroxylase, the rate-determining enzyme of bile acid synthesis. These experiments will be conducted initially in animal models and the most promising leads will be followed up in man. The animal studies are designed to gain information concerning the sequence of individual steps in the biosynthesis of bile acids and the quantitative significance of specific pathways leading either to cholic acid or chenodeoxycholic acid. Emphasis will be placed on the stereospecificity of the side-chain oxidation of cholesterol.
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