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.

Public Health Relevance

Cholestatic liver diseases arise from impairment of bile formation and/or bile flow. Intrahepatic retention of cytotoxic bile acids can cause liver injury, and injury to bile ducts or hepatocytes can lead to abnormalities in liver biochemistry, periductular fibrosis, biliary fibrosis, cirrhosis, or hepatobiliary malignancy. This study will uncover for the first time a novel role of E2F1 as a gate keeper that controls critical genes in th bile acid signaling pathway.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Research Project (R01)
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Integrative Nutrition and Metabolic Processes Study Section (INMP)
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Sherker, Averell H
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University of Utah
Internal Medicine/Medicine
Schools of Medicine
Salt Lake City
United States
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Lee, Sang Min; Zhang, Yuxia; Tsuchiya, Hiroyuki et al. (2015) Small heterodimer partner/neuronal PAS domain protein 2 axis regulates the oscillation of liver lipid metabolism. Hepatology 61:497-505
Zhang, Yuxia; Xu, Ningyi; Xu, Jun et al. (2014) E2F1 is a novel fibrogenic gene that regulates cholestatic liver fibrosis through the Egr-1/SHP/EID1 network. Hepatology 60:919-30
Myronovych, Andriy; Salazar-Gonzalez, Rosa-Maria; Ryan, Karen K et al. (2014) The role of small heterodimer partner in nonalcoholic fatty liver disease improvement after sleeve gastrectomy in mice. Obesity (Silver Spring) 22:2301-11
Yang, Zhihong; Tsuchiya, Hiroyuki; Zhang, Yuxia et al. (2013) MicroRNA-433 inhibits liver cancer cell migration by repressing the protein expression and function of cAMP response element-binding protein. J Biol Chem 288:28893-9
Smalling, Rana L; Delker, Don A; Zhang, Yuxia et al. (2013) Genome-wide transcriptome analysis identifies novel gene signatures implicated in human chronic liver disease. Am J Physiol Gastrointest Liver Physiol 305:G364-74
Zhang, Yuxia; Wang, Li (2013) Characterization of the mitochondrial localization of the nuclear receptor SHP and regulation of its subcellular distribution by interaction with Bcl2 and HNF4*. PLoS One 8:e68491
Yang, Zhihong; Zhang, Yuxia; Wang, Li (2013) A feedback inhibition between miRNA-127 and TGF*/c-Jun cascade in HCC cell migration via MMP13. PLoS One 8:e65256
Yang, Zhihong; Zhang, Yuxia; Wang, Li (2012) Mdm2 is a novel activator of ApoCIII promoter which is antagonized by p53 and SHP inhibition. Biochem Biophys Res Commun 417:744-6
Zhang, Yuxia; Andrews, Glen K; Wang, Li (2012) Zinc-induced Dnmt1 expression involves antagonism between MTF-1 and nuclear receptor SHP. Nucleic Acids Res 40:4850-60
Zhang, Yuxia; Wang, Li (2011) Nuclear receptor SHP inhibition of Dnmt1 expression via ERR?. FEBS Lett 585:1269-75

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