The conversion of cholesterol to bile acids is a major pathway for the disposal of excess cholesterol in the body. The first and rate-limiting step of bile acid synthesis in the liver is catalyzed by cholesterol 7alpha-hydroxylase, a specific cytochrome P-450 isozyme located in the membrane of the endoplasmic reticulum. This enzyme is thought to be regulated by bile acids returning to the liver via enterohepatic recirculation, dietary and de novo synthesized cholesterol and hormones. However, the molecular mechanism by which these agents regulate cholesterol 7alpha-hydroxylase gene is unknown at present. Recent progress in the purification and cloning of cholesterol 7alpha-hydroxylase has allowed us to demonstrate that bile acids, cholesterol and thyroid hormones regulate the transcription of cholesterol 7alpha-hydroxylase gene.
The specific aims are 1) to study the transcriptional regulation by bile acids, cholesterol, thyroid and glucocorticoid hormones in animal models and in the primary hepatocytes; 2) to identify cis-regulating elements in the promotor region and trans-acting factors, DNase I footprinting, gel retardation assay and the transcriptional regulation of promotor/reporter chimeric gene constructs will be performed; 3) to study the gene regulation by thyroid hormones, thyroid responsive elements in the gene will be examined. Our long-range goals are to understand the gene regulation of this important regulatory enzyme in bile acid synthesis, its roles in the regulation of cholesterol homeostasis and in human diseases involving abnormal bile acid synthesis, and cholesterol homeostasis such as hypercholesterolemia, atherosclerosis, gallstone disease and liver cirrhosis.
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