New pathways regulating bile acid homeostasis and cholestatic liver diseases

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DESCRIPTION (provided by applicant): The conversion to bile acids represents a major pathway for cholesterol elimination from the body, which is therefore of critical importance in maintaining cholesterol homeostasis. At least two pathways of bile acid biosynthesis exist in mammalian liver. The major neutral pathway is initiated by Cyp7a1, followed by Cyp8b1. The additional acidic pathway is initiated by Cyp27. Impairment of bile formation and/or bile flow will cause intrahepatic retention of cytotoxic bile acids, leading to liver injury to bile ducts and hepatocytes, and resulting in cholestatic liver diseases. Although it is well established that nuclear receptors are important transcriptional regulators of bile acid synthetic enzymes, there is a critical unmet need to identify new players that control bile acid homeostasis in order to better understand the molecular basis of cholestatic liver diseases. Based on our extensive in vitro and in vivo preliminary results generated during the current grant cycle, we have uncovered a novel role for the transcription factor E2F1 in the regulation of bile acid metabolism. Previously E2F1 has been shown to play a role in cell cycle progression, apoptosis, and adipocyte and beta cell function. In light of our preliminary results, it is imperative to explore the critical fnction of E2F1 in cholestatic liver fibrosis. The proposed research is significant because it uncovers for the first time E2F1 as a gate keeper that regulates key genes in the bile acid signaling pathway. The overall objective of this proposal is to understand the critical role of the E2F1 transcription factor in the development of cholestatic liver fibrosis through two distinct mechanisms: 1) a unique biphasic regulation of Egr-1 (early growth response 1) expression to control cholestatic liver inflammation and injury; and 2) a direct regulation of SHP (small heterodimer partner) and Cyp7a1 (cholesterol 7 alpha-hydroxylase)/Cyp8b1 (12- alpha-hydroxylase) expression to control bile acid biosynthesis and metabolism. The central hypothesis of this application, based on our Preliminary Results, is that E2F1 is a new player that controls bile acid homeostasis by transcriptional regulation of key genes in the bile acid signaling pathway. We propose that E2F1 is at the center of a regulatory network that coordinately controls bile acid levels. Specifically, E2F1 functions as both a positive regulator of Egr-1 and Cyp7a1/Cyp8b1 expression, and a negative regulator of SHP gene expression. E2F1 repression of SHP diminishes SHP inhibition of Egr-1 and Cyp7a1/8b1, which reinforces E2F1 activity. Induction of bile acids by the E2F1/Cyp7a1/8b1 cascade further enhances Egr-1 activation by E2F1 via FXR. The Specific Aims are: 1) To elucidate the role of E2F1 in cholestatic liver fibrosis via a biphasic regulation f Egr-1, and 2) To elucidate the role of E2F1 in bile acid homeostasis via cross-talk with SHP and Cyp7a1/Cyp8b1. Fully defining the regulation of bile acid metabolism, including bile acid synthesis and catabolism, is essential for further advances in diagnosis, management, and prevention of cholestatic liver diseases.