Interplay between metabolism and FXR activation in scoparone signaling


Principal Investigator: Bingfang Yan
Abstract: Scoparone is a coumarin derivative and structurally belongs to the superfamily of polyphenolic compounds. This compound is abundant in Yin Chin (artemisiae scopariae), a Chinese herb that has been used for thousands of years to treat liver and kidney diseases. Yin Chin preparations have received much attention worldwide lately and are marketed as health supplements in North America. Scoparone is recognized as a major hepatic protective compound and has been shown to induce mouse uridine diphosphate-5[unreadable]-glucuronosyltransferase-1A1 (UGT1A1), a bilirubin detoxification enzyme. We recently made an effort to test whether scoparone also induces human UGT1A1. Human primary hepatocytes were treated with scoparone or along with chenodeoxycholic acid (CDCA), an activator of the farnesoid X receptor (FXR). To our surprise, scoparone did not induce human UGT1A1, but instead significantly potentiated CDCA in inducing the bile salt export pump (BSEP). This biliary transporter is a target of CDCA-FXR signaling and plays an essential role in the secretion of bile acids. Consistent with the potentiation of BSEP induction, scoparone enhanced CDCA in activating FXR and the enhancement was much reduced with FXR phosphorylation-deficient mutants. In contrast, the enhancement was significantly increased in cells transfected with cytochrome P450 1A2 (CYP1A2), a drug-metabolizing enzyme. The central hypothesis of this project is that scoparone metabolites confer potent hepatic protection against cholestasis by efficaciously modulating FXR phosphorylation. The specific aims are: (1) to determine the potentiation of BSEP induction as a function of scoparone metabolism;(2) to characterize the phosphorylation of FXR by scoparone;and (3) to define the role of the FXR and scoparone metabolism interplay in anti-cholestasis. To determine the metabolism of scoparone in general population, a large number of individual liver samples will be tested for the metabolism of scoparone. The major metabolites will be structurally determined and tested for the potentiation of BSEP induction. To test whether scoparone is a modulator of the phosphorylation of FXR, hepatocytes will be treated with scoparone alone or plus CDCA, and the phosphorylation status of FXR will be analyzed. To ascertain the anti-cholestatic potential of scoparone, mice will be subjected to inducing cholestasis with or without scoparone, and cholestatic markers and the metabolism of scoparone will be monitored. Overall, the proposed studies will establish the metabolic pathway of scoparone and the significance of the metabolism in bile acid elimination. Cholestasis is the most common form of hepatotoxicity, and the scoparone-rich herb Yin Chin has long been used to normalize liver functions. These studies will provide important information on how the hepatic protective activity is achieved. In addition, FXR is recognized as an important metabolic regulator and has anti-inflammatory effect. Interestingly, scoparone has been found to exert these very activities. Thus, a confirmation on the functional connection between FXR and scoparone will have broad mechanistic and therapeutic implications.
Funding Period: 2013-09-01 - 2016-08-31
more information: NIH RePORT

Top Publications

  1. pmc A comparative study of hollow copper sulfide nanoparticles and hollow gold nanospheres on degradability and toxicity
    Liangran Guo
    Department of Biomedical and Pharmaceutical Sciences, College of Pharmacy, The University of Rhode Island, Kingston, Rhode Island 02881, United States
    ACS Nano 7:8780-93. 2013

Detail Information


  1. pmc A comparative study of hollow copper sulfide nanoparticles and hollow gold nanospheres on degradability and toxicity
    Liangran Guo
    Department of Biomedical and Pharmaceutical Sciences, College of Pharmacy, The University of Rhode Island, Kingston, Rhode Island 02881, United States
    ACS Nano 7:8780-93. 2013
    ..The comparative results between the two types of nanoparticles will advance the development of HCuSNPs as a new class of biodegradable inorganic nanomaterials for photothermal therapy. ..

Research Grants30

  1. Role of Bile Acids in the Initiation of Liver Regeneration
    Willscott E Naugler; Fiscal Year: 2013
  2. Regulation of Hepatic Metabolic Function by Parenteral Nutrition
    Douglas G Burrin; Fiscal Year: 2013
    ..These studies in premature pigs are highly translational and will lead to new clinical practices in nutritional support and prevention of liver disease in infants. ..
  3. Host-pathogen competition in IFN mediated antiviral defense
    Jae U Jung; Fiscal Year: 2013
  4. A 3D biomimetic liver sinusoid construct for predicting physiology and toxicity
    Martin L Yarmush; Fiscal Year: 2013
    ..This module will be designed to integrate with other organ models forming a human microphysiology platform to improve drug efficacy and safety testing. ..
  5. Signaling-pathway-based preventative strategies for alcoholic liver disease
    Albert J Fornace; Fiscal Year: 2013
    ..Results will improve approaches to prevent or treat alcoholic liver disease with a solid mechanistic rationale. ..
  6. B Cells in Health and Disease
    IGNACIO E SANZ; Fiscal Year: 2013
    ..Finally, and central to this PPG, our results will greatly enhance our ability to design better and safer BCDT therapies and to develop biomarkers of B cell targeted treatments efficacy and safety. ..
  7. The Wake Forest Center for Botanical Lipids and Inflammatory Disease Prevention
    Floyd H Chilton; Fiscal Year: 2013
    Gary H Perdew; Fiscal Year: 2013
    ..The attenuation of cholesterol synthesis through the use of SAhRM has the potential to impact a variety of diseases, such as atherosclerosis and nonalcoholic fatty liver disease. ..
  9. The Perinatal Pharmacology of the Nuclear Receptor
    Wen Xie; Fiscal Year: 2013
    ..This applicant agrees and has requested funds to participate in the annual NIH-sponsored two-day meetings focusing on Developmental Pharmacology in Bethesda, MD. This applicant also agrees to cooperate with other investigators. ..
  10. Epigenetic regulation of liver transporters
    Frederick J Suchy; Fiscal Year: 2013
    ..These studies will provide insight into an unexplored area of hepatic biology and pathobiology, and suggest potential new targets for drug development. ..
  11. Molecular Mechanisms of Intrahepatic Cholestasis
    Benjamin L Shneider; Fiscal Year: 2013
    ..Recent molecular discoveries provide an opportunity to understand this disease (providing new therapies) and to explore basic physiology of the liver, pancreas, gastrointestinal tract and lungs. ..
  12. Regulation of Hepatic P450s by Anti-Cholesterol Drugs
    Thomas A Kocarek; Fiscal Year: 2013
    ..Therefore alternative anti-cholesterol drugs are needed. The public health relevance of this project is that it will increase our knowledge about the potential utility of a novel class of anti-cholesterol drugs. ..
  13. Mechanisms Regulating Non-biliary Fecal Sterol Loss
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  14. Histamine modulation of biliary proliferation and damage
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    ..synthesis may be important in the inhibition of biliary hyperplasia, overexpression of HDC (leading to enhanced histamine release) may be key for stimulating biliary proliferation in ductopenic conditions associated with biliary damage ..
  15. Neonatal hyperbilirubinemia in a humanized UGT1 animal model
    Robert H Tukey; Fiscal Year: 2013
    ..This knowledge and information will serve as the foundation for examining new therapies and potential treatments to reduce the incidence of bilirubin induced toxicities in humans. ..
  16. Control of Sterol and Lipoprotein Homeostasis by miRNA
    Angel Baldán; Fiscal Year: 2013
    ..The results of these studies might lead to novel, improved ways to manage patients with hypercholesterolemia and/or patients with cholestasis. ! ..
  17. Inflammatory responses of vascular cells
    Paul L Fox; Fiscal Year: 2013
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  18. PAHs: New Technologies and Emerging Health Risks
    David E Williams; Fiscal Year: 2013
    ..Accomplishing these goals will provide significant scientific advancement and improve the quality of life for impacted communities. ..
  19. Hepatic Cholesteryl Ester Metabolism and Cholesterol Elimination
    Shobha Ghosh; Fiscal Year: 2013
    ..Aim 4: To obtain in vivo "proof of concept" by liver-specific targeted disruption of CEH in mice and to determine its effect on intracellular CE metabolism and atherosclerosis. ..
  20. Ca2+ Waves in Hepatocytes: Mechanisms and Effects
    Michael H Nathanson; Fiscal Year: 2013
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    ..Drugs targeting to nuclear receptor and signaling pathways, and miRNA antagomirs may be developed for treating metabolic liver diseases. ..