Bile acids are physiological detergents that generate bile flow and facilitate intestine absorption and transport of lipids, nutrients and vitamins. Bile acids also are signaling molecules and inflammatory agents that rapidly activate nuclear receptors and a complex network of cell signaling pathways that regulate lipid and glucose metabolism. Despite intense research in recent years, the molecular mechanism of bile acid feedback inhibition of bile acid synthesis remains obscure. It is thought that bile acids activate a nuclear receptor, farnesoid X receptor (FXR) that induces small heterodimer partner (SHP), which inhibits transcription of the CYP7A1 gene encoding cholesterol 71-hydroxylase (CYP7A1), the first and rate-limiting enzyme in bile acid synthesis in the liver. Recent studies have discovered a FXR induced intestinal hormone, fibroblast growth factor 15 (FGF15) (or FGF19 in human) that activates FGF receptor 4 (FGFR4) signaling in mouse liver to inhibit bile acid synthesis. However, the mechanism by which the FXR/FGF19/FGFR4 signaling pathway inhibits CYP7A1 remains unknown. The central hypothesis is that bile acids and FXR regulate CYP7A1 gene expression via activation of an intricate network of nuclear receptor cell signaling pathways that regulate CYP7A1 gene transcription, and that micro RNAs may play a role in post-transcriptional regulation of the human CYP7A1 gene.
Three specific aims are: 1. Study the mechanism of FGF19/FGFR4 regulation of CYP7A1 and bile acid synthesis in human hepatocytes. 2. Study microRNA regulation of CYP7A1 and bile acid synthesis in human hepatocytes. 3. Study the role of CYP7A1 in control of hepatic inflammation and lipid metabolism. The overall objective of this study is to elucidate the molecular mechanism of bile acid-activated nuclear receptor and cell signaling pathways in regulation of CYP7A1 and bile acid synthesis in liver health and diseases. Dysregulation of bile acid metabolism causes cholestatic liver injury and contributes to liver cirrhosis, steatosis, dyslipidemia, diabetes, obesity, and atherosclerosis. Drugs targeting to nuclear receptor and signaling pathways, and miRNA antagomirs may be developed for treating metabolic liver diseases.
Bile acids are physiological lipid molecules required for absorption of nutrients, transport of lipid and steroids, and disposal of toxic and xenobiotics. Bile acids also are signaling molecules that activate nuclear receptors and cell signaling pathways to regulate lipid and glucose homeostasis. Bile acid synthesis is tightly regulated at the first and rate-limiting enzyme CYP7A1 by a bile acid feedback mechanism. The molecular mechanism of bile acid feedback inhibition of CYP7A1 remains unclear. The proposed specific aims are designed to elucidate the molecular mechanism of bile acid-activated nuclear receptor FXR signaling in transcription and post- transcriptional regulation of the human CYP7A1 gene. The project is highly relevant to prevention and treatment of hepatobiliary diseases, diabetes, obesity and atherosclerosis.
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