Bile acids are mainly produced in the liver with cholesterol 7a hydroxylase (cyp7a1) the rate-limiting enzyme. Bile acids are involved in liver, biliary, intestinal, and cardiovascular diseases. FXR is a bile-acid activated nuclear receptor and is essential in maintaining bile-acid homeostasis. FXR dysfunction contributes to the development of cholestasis, gallstones, fatty-liver disease, and liver tumor. Emerging evidence suggest that in mice FXR suppresses cyp7a1 gene expression via pathways initiated both in the liver and the intestine. However, to understand the roles of FXR in suppressing bile-acid synthesis, clear gaps exist in consolidating where the suppressive pathway initiates, to what extent SHP and FGF15 are involved, and what signaling molecules are in the liver to suppress cyp7a1 gene expression. The objective of this application is to establish the underlying molecular mechanism by which FXR regulates bile-acid synthesis in a tissue-specific manner. My hypothesis is that intestine-initiated FGF15- FGR4 pathway is the major and the liver-initiated SHP-LRH-1 cascade is a minor underlying mechanism for suppressing cyp7a1 with FXR activation, in addition, both Egr-1 and cJun are involved in FGFR4 pathway to suppress cyp7a1 gene expression. The hypothesis is based on our compelling preliminary data that collectively showed that FXR, but not SHP, intestinal FXR, but not hepatic FXR, is mainly responsible for the suppression of cyp7a1 gene expression. We plan to test the hypothesis and accomplish the objective by pursuing the following specific aims. (1) Establish the tissue-specific function of FXR in suppressing cyp7a1 gene expression. (2) Determine to what extent that SHP and FGF15 are involved in suppressing cyp7a1 and regulating bile-acid homeostasis. (3) Elucidate the signaling pathways for suppressing cyp7a1 gene expression following FGFR4 activation. The proposed research is innovative and represents a paradigm shift in understanding the regulation of bile-acid synthesis. We are the first to combine the usage of tissue-specific FXR KO mice with cellular and molecular techniques to identify the fundamental pathways in regulating bile-acid feedback inhibition. These studies will identify the tissue specific roles of FXR, which will provide a fundamental understanding for the study of bile-acid, cholesterol, and triglyceride homeostasis. Furthermore, completion of the proposed study will shed light on designing tissue-specific FXR modulators in the future to better prevent and treat human diseases associated with bile-acid disorders. Public Health Relevance: Bile acids are the main components in bile and are important for regulating cholesterol and triglyceride homeostasis. FXR is essential in regulating bile-acid homeostasis, and contributes to the development of cholestasis, gallstones, fatty-liver disease, liver tumors, and atherosclerosis. Completion of the proposed study will shed light on designing tissue-specific FXR modulators in the future to better prevent and treat human diseases associated with bile-acid disorders.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Research Project (R01)
Project #
Application #
Study Section
Hepatobiliary Pathophysiology Study Section (HBPP)
Program Officer
Sherker, Averell H
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Rutgers University
Schools of Pharmacy
New Brunswick
United States
Zip Code
Schumacher, J D; Kong, B; Pan, Y et al. (2017) The effect of fibroblast growth factor 15 deficiency on the development of high fat diet induced non-alcoholic steatohepatitis. Toxicol Appl Pharmacol 330:1-8
Zhu, Yan; Liu, Hongxia; Zhang, Min et al. (2016) Fatty liver diseases, bile acids, and FXR. Acta Pharm Sin B 6:409-412
Schumacher, Justin D; Guo, Grace L (2015) Mechanistic review of drug-induced steatohepatitis. Toxicol Appl Pharmacol 289:40-7
Schmitt, Johannes; Kong, Bo; Stieger, Bruno et al. (2015) Protective effects of farnesoid X receptor (FXR) on hepatic lipid accumulation are mediated by hepatic FXR and independent of intestinal FGF15 signal. Liver Int 35:1133-1144
Zhan, Le; Liu, Hui-Xin; Fang, Yaping et al. (2014) Genome-wide binding and transcriptome analysis of human farnesoid X receptor in primary human hepatocytes. PLoS One 9:e105930
Kong, Bo; Huang, Jiansheng; Zhu, Yan et al. (2014) Fibroblast growth factor 15 deficiency impairs liver regeneration in mice. Am J Physiol Gastrointest Liver Physiol 306:G893-902
Kong, Bo; Guo, Grace L (2014) Soluble expression of disulfide bond containing proteins FGF15 and FGF19 in the cytoplasm of Escherichia coli. PLoS One 9:e85890
Li, Guodong; Zhu, Yan; Tawfik, Ossama et al. (2013) Mechanisms of STAT3 activation in the liver of FXR knockout mice. Am J Physiol Gastrointest Liver Physiol 305:G829-37
Swanson, Hollie I; Wada, Taira; Xie, Wen et al. (2013) Role of nuclear receptors in lipid dysfunction and obesity-related diseases. Drug Metab Dispos 41:1-11
Li, Guodong; Kong, Bo; Zhu, Yan et al. (2013) Small heterodimer partner overexpression partially protects against liver tumor development in farnesoid X receptor knockout mice. Toxicol Appl Pharmacol 272:299-305

Showing the most recent 10 out of 34 publications