Regulation of Bile Acid Synthesis by Nuclear Receptors

Summary

Principal Investigator: JOHN CHIANG
Abstract: Bile acids are physiological agents that facilitate absorption, transport and disposal of steroids, nutrients, metabolites and xenobiotics. Bile acids also are signaling molecules that activate nuclear receptors to regulate lipid and glucose homeostasis. Dysregulation of bile acid metabolism causes dyslipidemia, gallstone, liver, and cardiovascular diseases, and diabetes. Bile acids, insulin and cytokines inhibit CYP7A1, the first and rate-limiting enzyme of the bile acid synthesis pathway in the liver. The expression of CYP7A1 is mainly regulated at gene transcriptional level. Bile acid activates the FXR/SHP pathway, and several cell signaling pathways to inhibit CYP7A1 gene transcription. The mechanism of nuclear receptors and signaling pathways regulating CYP7A1 gene transcription remain to be elucidated. Most studies on CYP7A1 gene regulation have been performed in animal models. We have observed marked differences in regulation of the human and rodent CYP7A1 genes. Our central hypothesis is that as an acute phase response to inflammation and liver injury, bile acids and other stimuli activate the PI3K/AKT and MAP kinase signaling pathways, and signal crosstalk regulates nuclear receptors and co-regulators to remodel CYP7A1 and CYP8B1 chromatins. The specific aim 1 will study nuclear receptor and co-regulator modulation of CYP7A1 and CYP8B1 chromatin. The roles of HNF4? and FTP, and their co-regulators Prox1, PGC-1?, histone deacetylase (HDAC) and silencing information regulator (SIRT1) will be studied. HepG2 and primary human hepatocytes will be used for chromatin immunoprecipitation (ChIP), co-IP and mammalian two-hybrid assays to study DNA-protein and protein-protein interaction. Aim 2 will study the crosstalk of bile acid, cytokine, insulin, glucagon and PMA signaling pathways in regulating CYP7A1/CYP8B1 gene transcription. Real time PCR, siRNA, and microarrays will be used to identify genes involved in signaling crosstalk. Am 3 will study hepatocyte growth factor (HGF) regulation of CYP7A1 gene transcription to identify signaling pathway and crosstalk with insulin signaling. The objective of this research is to elucidate the molecular mechanism of nuclear receptor and signaling pathway regulation of bile acid synthesis. This study could contribute to understanding the mechanisms of metabolic diseases caused by dysregulation of bile acid synthesis and develop therapeutic agents to treat dyslipidemia, liver diseases, obesity and type II diabetes.
Funding Period: ----------------2000 - ---------------2011-
more information: NIH RePORT

Top Publications

  1. ncbi Glucagon and cAMP inhibit cholesterol 7alpha-hydroxylase (CYP7A1) gene expression in human hepatocytes: discordant regulation of bile acid synthesis and gluconeogenesis
    Kwang Hoon Song
    Department of Biochemistry and Molecular Pathology, Northeastern Ohio Universities College of Medicine, Rootstown, OH 44272, USA
    Hepatology 43:117-25. 2006
  2. pmc All-trans-retinoic acid ameliorates hepatic steatosis in mice by a novel transcriptional cascade
    Seong Chul Kim
    Department of Integrative Medical Sciences, Northeast Ohio Medical University, Rootstown, OH
    Hepatology 59:1750-60. 2014
  3. pmc Eicosanoids in metabolic syndrome
    James P Hardwick
    Biochemistry and Molecular Pathology, Department of Integrative Medical Sciences, Northeast Ohio Medical University, Rootstown, Ohio, USA
    Adv Pharmacol 66:157-266. 2013
  4. pmc Nuclear receptors in bile acid metabolism
    Tiangang Li
    Department of Integrative Medical Sciences, Northeast Ohio Medical University, Rootstown, Ohio 44272, USA
    Drug Metab Rev 45:145-55. 2013
  5. pmc Role of nuclear receptors in lipid dysfunction and obesity-related diseases
    Hollie I Swanson
    Department of Molecular and Biomedical Pharmacology, MS305, University of Kentucky College of Medicine, 800 Rose Street, Lexington, KY40536, USA
    Drug Metab Dispos 41:1-11. 2013
  6. pmc Estrogen-related receptor γ controls hepatic CB1 receptor-mediated CYP2E1 expression and oxidative liver injury by alcohol
    Don Kyu Kim
    National Creative Research Initiatives Center for Nuclear Receptor Signals, Hormone Research Center, Gwangju, Republic of Korea
    Gut 62:1044-54. 2013
  7. pmc Retinoic acid-related orphan receptor α regulates diurnal rhythm and fasting induction of sterol 12α-hydroxylase in bile acid synthesis
    Preeti Pathak
    From the Department of Integrative Medical Sciences, Northeast Ohio Medical University, Rootstown, Ohio 44272 and
    J Biol Chem 288:37154-65. 2013
  8. pmc TGFbeta1, TNFalpha, and insulin signaling crosstalk in regulation of the rat cholesterol 7alpha-hydroxylase gene expression
    Tiangang Li
    Department of Integrative Medical Sciences, Northeastern Ohio Universities Colleges of Medicine and Pharmacy, Rootstown, OH 44272, USA
    J Lipid Res 49:1981-9. 2008
  9. ncbi Hepatocyte growth factor signaling pathway inhibits cholesterol 7alpha-hydroxylase and bile acid synthesis in human hepatocytes
    Kwang Hoon Song
    Department of Microbiology, Immunology and Biochemistry, Northeastern Ohio Universities College of Medicine, Rootstown, OH 44272, USA
    Hepatology 46:1993-2002. 2007
  10. ncbi A novel role of transforming growth factor beta1 in transcriptional repression of human cholesterol 7alpha-hydroxylase gene
    Tiangang Li
    Department of Microbiology, Immunology and Biochemistry, Northeastern Ohio University, College of Medicine, Rootstown, Ohio, USA
    Gastroenterology 133:1660-9. 2007

Scientific Experts

  • JOHN CHIANG
  • Tiangang Li
  • Kwang Hoon Song
  • Dipanjan Chanda
  • Hueng Sik Choi
  • Don Kyu Kim
  • Chul Ho Lee
  • Yong Hoon Kim
  • Stephen Strom
  • Seung Hoi Koo
  • Shuxin Han
  • Erika Owsley
  • Ewa Ellis
  • James P Hardwick
  • Quan Shang
  • Yoon Kwang Lee
  • Huiyan Ma
  • Seong Chul Kim
  • Hollie I Swanson
  • Preeti Pathak
  • Bo Kong
  • David D Moore
  • Xuemei Ge
  • Jagannath Misra
  • Yanqiao Zhang
  • Michelle Matozel
  • Ji Min Lee
  • Jung Ran Noh
  • Luxing Pan
  • Monica Saumoy
  • Guorong Xu
  • G Stephen Tint
  • Gerald Salen
  • Wanjin Tang
  • Aaron Cook
  • Nicole Smallwood
  • Mikang Lee
  • David Axe
  • Chun Ki Kim
  • Seung Bum Park
  • Andrew Esterle
  • William M Chilian
  • Eleonora Distrutti
  • Jung Ran Kim
  • Muralimohan Yepuru
  • Grace L Guo
  • Chul Ho Yun
  • Won Il Jeong
  • Katie Eckman
  • Ramesh Narayanan
  • Angela Zampella
  • Barbara Renga
  • Wen Xie
  • James T Dalton
  • Mohamed A Abdelmegeed
  • Stefano Fiorucci
  • Tae Sik Park
  • JinYoung Park
  • Hyun Hee Jang
  • Minseob Koh
  • Byoung Joon Song
  • Ann M Thomas
  • Taira Wada
  • Liya Yin
  • Lisa Mari Nilsson
  • Shannon Boehme
  • Grace Guo
  • Sung Hoon Back
  • Colleen M Novak
  • Dongryeol Ryu
  • Peter Hsu
  • Min Woo Lee
  • Yong Deuk Kim
  • Woo Young Seo
  • Minho Shong
  • Gi Ryang Kweon
  • Kyeong Hoon Jeong
  • Young Joo Park
  • Ji Hoon Park
  • Jeonggu Sim
  • Goo Taeg Oh
  • Mi Ran Lee
  • In Kyu Lee
  • Jung Hwan Hwang
  • Wenling Chen
  • Gosta Eggertsen
  • Maria Norlin
  • Asmeen Jahan
  • Xiaoying Kong

Detail Information

Publications34

  1. ncbi Glucagon and cAMP inhibit cholesterol 7alpha-hydroxylase (CYP7A1) gene expression in human hepatocytes: discordant regulation of bile acid synthesis and gluconeogenesis
    Kwang Hoon Song
    Department of Biochemistry and Molecular Pathology, Northeastern Ohio Universities College of Medicine, Rootstown, OH 44272, USA
    Hepatology 43:117-25. 2006
    ..In conclusion, this study unveils a species difference in nutrient regulation of the human and mouse CYP7A1 gene and suggests a discordant regulation of bile acid synthesis and gluconeogenesis by glucagon in human livers during fasting...
  2. pmc All-trans-retinoic acid ameliorates hepatic steatosis in mice by a novel transcriptional cascade
    Seong Chul Kim
    Department of Integrative Medical Sciences, Northeast Ohio Medical University, Rootstown, OH
    Hepatology 59:1750-60. 2014
    ....
  3. pmc Eicosanoids in metabolic syndrome
    James P Hardwick
    Biochemistry and Molecular Pathology, Department of Integrative Medical Sciences, Northeast Ohio Medical University, Rootstown, Ohio, USA
    Adv Pharmacol 66:157-266. 2013
    ..This review focuses on the mechanisms linking eicosanoid metabolism to persistent inflammation and altered lipid and carbohydrate metabolism in MetS...
  4. pmc Nuclear receptors in bile acid metabolism
    Tiangang Li
    Department of Integrative Medical Sciences, Northeast Ohio Medical University, Rootstown, Ohio 44272, USA
    Drug Metab Rev 45:145-55. 2013
    ..Bile-acid-based drugs targeting nuclear receptors are in clinical trials for treating cholestatic liver diseases and fatty liver disease...
  5. pmc Role of nuclear receptors in lipid dysfunction and obesity-related diseases
    Hollie I Swanson
    Department of Molecular and Biomedical Pharmacology, MS305, University of Kentucky College of Medicine, 800 Rose Street, Lexington, KY40536, USA
    Drug Metab Dispos 41:1-11. 2013
    ..Taken together, the significant findings reported during this symposium illustrate the promise associated with targeting a number of nuclear receptors for the development of new therapies to treat obesity and other metabolic disorders...
  6. pmc Estrogen-related receptor γ controls hepatic CB1 receptor-mediated CYP2E1 expression and oxidative liver injury by alcohol
    Don Kyu Kim
    National Creative Research Initiatives Center for Nuclear Receptor Signals, Hormone Research Center, Gwangju, Republic of Korea
    Gut 62:1044-54. 2013
    ..The nuclear hormone receptor oestrogen-related receptor γ (ERRγ) is a constitutively active transcriptional activator regulating gene expression...
  7. pmc Retinoic acid-related orphan receptor α regulates diurnal rhythm and fasting induction of sterol 12α-hydroxylase in bile acid synthesis
    Preeti Pathak
    From the Department of Integrative Medical Sciences, Northeast Ohio Medical University, Rootstown, Ohio 44272 and
    J Biol Chem 288:37154-65. 2013
    ..Antagonizing RORα activity may be a therapeutic strategy for treating inflammatory diseases such as non-alcoholic fatty liver disease and type 2 diabetes. ..
  8. pmc TGFbeta1, TNFalpha, and insulin signaling crosstalk in regulation of the rat cholesterol 7alpha-hydroxylase gene expression
    Tiangang Li
    Department of Integrative Medical Sciences, Northeastern Ohio Universities Colleges of Medicine and Pharmacy, Rootstown, OH 44272, USA
    J Lipid Res 49:1981-9. 2008
    ..The crosstalk of insulin, TGFbeta and TNFalpha signaling pathways may regulate bile acid synthesis and lipid homeostasis in diabetes, fatty liver disease, and liver fibrosis...
  9. ncbi Hepatocyte growth factor signaling pathway inhibits cholesterol 7alpha-hydroxylase and bile acid synthesis in human hepatocytes
    Kwang Hoon Song
    Department of Microbiology, Immunology and Biochemistry, Northeastern Ohio Universities College of Medicine, Rootstown, OH 44272, USA
    Hepatology 46:1993-2002. 2007
    ....
  10. ncbi A novel role of transforming growth factor beta1 in transcriptional repression of human cholesterol 7alpha-hydroxylase gene
    Tiangang Li
    Department of Microbiology, Immunology and Biochemistry, Northeastern Ohio University, College of Medicine, Rootstown, Ohio, USA
    Gastroenterology 133:1660-9. 2007
    ..The objective of this study is to investigate the role of TGFbeta1 in hepatic bile acid synthesis...
  11. ncbi An overlapping binding site in the CYP7A1 promoter allows activation of FXR to override the stimulation by LXRalpha
    Quan Shang
    Department of Medicine, University of Medicine and Dentistry of New Jersey, New Jersey Medical School, Newark, New Jersey, USA
    Am J Physiol Gastrointest Liver Physiol 293:G817-23. 2007
    ....
  12. pmc Insulin regulation of cholesterol 7alpha-hydroxylase expression in human hepatocytes: roles of forkhead box O1 and sterol regulatory element-binding protein 1c
    Tiangang Li
    Department of Microbiology, Immunology and Biochemistry, Northeastern Ohio University College of Medicine, Rootstown, Ohio 44272, USA
    J Biol Chem 281:28745-54. 2006
    ..Insulin may play a major role in the regulation of bile acid synthesis and dyslipidemia in diabetes...
  13. pmc Bile acids and cytokines inhibit the human cholesterol 7 alpha-hydroxylase gene via the JNK/c-jun pathway in human liver cells
    Tiangang Li
    Department of Microbiology, Immunology, and Biochemistry, Northeastern Ohio Universities College of Medicine, Rootstown, OH 44272, USA
    Hepatology 43:1202-10. 2006
    ..The JNK/c-Jun signaling pathway inhibits bile acid synthesis and protects hepatocytes against the toxic effect of inflammatory agents...
  14. ncbi Estrogen-mediated regulation of CYP7B1: a possible role for controlling DHEA levels in human tissues
    Wanjin Tang
    Department of Pharmaceutical Biosciences, Division of Biochemistry, University of Uppsala, Box 578, S 751 23 Uppsala, Sweden
    J Steroid Biochem Mol Biol 100:42-51. 2006
    ..Regulation by estrogens may also be of importance in other processes where CYP7B1 is involved, including cholesterol homeostasis, cellular proliferation, and CNS function...
  15. ncbi The stimulatory effect of LXRalpha is blocked by SHP despite the presence of a LXRalpha binding site in the rabbit CYP7A1 promoter
    Quan Shang
    Department of Medicine, University of Medicine and Dentistry of New Jersey, New Jersey Medical School, Newark, 07103, USA
    J Lipid Res 47:997-1004. 2006
    ..Although FTF is a competent factor for maintaining baseline activity, it does not further enhance and may suppress CYP7A1 transcription...
  16. pmc A Prospero-related homeodomain protein is a novel co-regulator of hepatocyte nuclear factor 4alpha that regulates the cholesterol 7alpha-hydroxylase gene
    Kwang Hoon Song
    Department of Microbiology, Immunology and Biochemistry, Northeastern Ohio University College of Medicine, 4209 State Route 44, Rootstown, OH 44272, USA
    J Biol Chem 281:10081-8. 2006
    ..These results suggest that Prox1 is a novel co-regulator of HNF4alpha that may play a key role in the regulation of bile acid synthesis and gluconeogenesis in the liver...
  17. pmc Rifampicin induction of CYP3A4 requires pregnane X receptor cross talk with hepatocyte nuclear factor 4alpha and coactivators, and suppression of small heterodimer partner gene expression
    Tiangang Li
    Department of Biochemistry and Molecular Pathology, Northeastern Ohio University College of Medicine, Rootstown, 44272, USA
    Drug Metab Dispos 34:756-64. 2006
    ..PXR concomitantly inhibits SHP gene transcription and maximizes the PXR induction of the CYP3A4 gene in human livers. Drugs targeted to PXR may be developed for treating cholestatic liver diseases induced by bile acids and drugs...
  18. ncbi PXR induces CYP27A1 and regulates cholesterol metabolism in the intestine
    Tiangang Li
    Department of Microbiology, Immunology, and Biochemistry, Northeastern Ohio Universities College of Medicine, Rootstown, OH 44272, USA
    J Lipid Res 48:373-84. 2007
    ..This study suggests an intestine-specific PXR/CYP27A1/LXRalpha pathway that regulates intestine cholesterol efflux and HDL assembly...
  19. pmc Curcumin differentially regulates endoplasmic reticulum stress through transcriptional corepressor SMILE (small heterodimer partner-interacting leucine zipper protein)-mediated inhibition of CREBH (cAMP responsive element-binding protein H)
    Jagannath Misra
    Center for Nuclear Receptor Signals, Hormone Research Center, School of Biological Science and Technology, Chonnam National University, Gwangju 500 757, Republic of Korea
    J Biol Chem 286:41972-84. 2011
    ..Overall, for the first time we suggest a novel phenomenon that the curcumin/LKB1/AMPK/SMILE/PGC1α pathway differentially regulates ER stress-mediated gene transcription...
  20. pmc Cannabinoid receptor type 1 (CB1R) signaling regulates hepatic gluconeogenesis via induction of endoplasmic reticulum-bound transcription factor cAMP-responsive element-binding protein H (CREBH) in primary hepatocytes
    Dipanjan Chanda
    National Creative Research Initiatives Center for Nuclear Receptor Signals, Hormone Research Center, School of Biological Sciences and Technology, Chonnam National University, Gwangju 500 757, Republic of Korea
    J Biol Chem 286:27971-9. 2011
    ....
  21. pmc Aldo-keto reductase 1B7 is a target gene of FXR and regulates lipid and glucose homeostasis
    Xuemei Ge
    Department of Integrative Medical Sciences, Northeast Ohio Medical University, Rootstown, OH, USA
    J Lipid Res 52:1561-8. 2011
    ..AKR1B7 may be a therapeutic target for treatment of fatty liver disease associated with diabetes mellitus...
  22. pmc Overexpression of cholesterol 7α-hydroxylase promotes hepatic bile acid synthesis and secretion and maintains cholesterol homeostasis
    Tiangang Li
    Department of Integrative Medical Sciences, Northeastern Ohio University s Colleges of Medicine and Pharmacy, Rootstown, OH, USA
    Hepatology 53:996-1006. 2011
    ....
  23. pmc AMPK-dependent repression of hepatic gluconeogenesis via disruption of CREB.CRTC2 complex by orphan nuclear receptor small heterodimer partner
    Ji Min Lee
    Hormone Research Center, School of Biological Sciences and Technology, Chonnam National University, Gwangju 500 757, Republic of Korea
    J Biol Chem 285:32182-91. 2010
    ..In conclusion, our results suggest that a delayed effect of metformin-mediated induction of SHP gene expression inhibits CREB-dependent hepatic gluconeogenesis...
  24. pmc Transgenic expression of cholesterol 7alpha-hydroxylase in the liver prevents high-fat diet-induced obesity and insulin resistance in mice
    Tiangang Li
    Department of Integrative Medical Sciences, Northeastern Ohio Universities Colleges of Medicine and Pharmacy, Rootstown, OH 44272, USA
    Hepatology 52:678-90. 2010
    ..HFD-fed Cyp7a1-tg mice had increased whole body energy expenditure and induction of fatty acid oxidation genes in the brown adipose tissue...
  25. pmc Bile acids activate fibroblast growth factor 19 signaling in human hepatocytes to inhibit cholesterol 7alpha-hydroxylase gene expression
    Kwang Hoon Song
    Department of Integrative Medical Sciences, Northeastern Ohio Universities Colleges of Medicine and Pharmacy, Rootstown, OH 44272, USA
    Hepatology 49:297-305. 2009
    ..FGF19 antibody and siRNA specific to FGFR4 abrogated GW4064 inhibition of CYP7A1. These results suggest that bile acid-activated FXR is able to induce FGF19 in hepatocytes to inhibit CYP7A1 by an autocrine/paracrine mechanism...
  26. pmc Mechanism of vitamin D receptor inhibition of cholesterol 7alpha-hydroxylase gene transcription in human hepatocytes
    Shuxin Han
    Department of Integrative Medical Sciences, Northeastern Ohio Universities Colleges of Medicine and Pharmacy, 4209 State Route 44, Rootstown, OH 44272, USA
    Drug Metab Dispos 37:469-78. 2009
    ..This study shows that VDR is expressed in human hepatocytes and may play a critical role in the inhibition of bile acid synthesis, thus protecting liver cells during cholestasis...
  27. pmc Hepatocyte nuclear factor 4alpha regulation of bile acid and drug metabolism
    John Y L Chiang
    Northeastern Ohio Universities Colleges of Medicine and Pharmacy, Department of Integrative Medical Sciences, Rootstown, Ohio 44272, USA
    Expert Opin Drug Metab Toxicol 5:137-47. 2009
    ..Drugs that specifically activate HNF4alpha could be developed for treating metabolic diseases such as diabetes, dyslipidemia and cholestasis, as well as drug metabolism and detoxification...
  28. pmc Bile acids: regulation of synthesis
    John Y L Chiang
    Department of Integrative Medical Sciences, Northeastern Ohio University s Colleges of Medicine and Pharmacy, Rootstown, OH 44272, USA
    J Lipid Res 50:1955-66. 2009
    ..Bile acids and bile acid receptors are therapeutic targets for development of drugs for treatment of cholestatic liver diseases, fatty liver diseases, diabetes, obesity, and metabolic syndrome...
  29. pmc Forkhead box transcription factor O1 inhibits cholesterol 7alpha-hydroxylase in human hepatocytes and in high fat diet-fed mice
    Tiangang Li
    Department of Integrative Medical Sciences, Northeastern Ohio Universities Colleges of Medicine and Pharmacy, 4209 State Route 44, Rootstown, OH 44272, USA
    Biochim Biophys Acta 1791:991-6. 2009
    ..Impaired regulation of FoxO1 may cause down-regulation of CYP7A1 gene expression and contribute to dyslipidemia in insulin resistance...
  30. pmc Hepatocyte growth factor family negatively regulates hepatic gluconeogenesis via induction of orphan nuclear receptor small heterodimer partner in primary hepatocytes
    Dipanjan Chanda
    Hormone Research Center, School of Biological Sciences and Technology, Chonnam National University, Gwangju 500 757, Republic of Korea
    J Biol Chem 284:28510-21. 2009
    ..Overall, our results suggest a novel signaling pathway through HGF/AMPK/USF-1/SHP to inhibit hepatic gluconeogenesis...
  31. pmc Glucose stimulates cholesterol 7alpha-hydroxylase gene transcription in human hepatocytes
    Tiangang Li
    Department of Integrative Medical Sciences, Northeastern Ohio Universities Colleges of Medicine and Pharmacy, Rootstown, OH 44272, USA
    J Lipid Res 51:832-42. 2010
    ..Glucose induction of bile acid synthesis may have an important implication in metabolic control of glucose, lipid, and energy homeostasis under normal and diabetic conditions...
  32. pmc A putative role of micro RNA in regulation of cholesterol 7alpha-hydroxylase expression in human hepatocytes
    Kwang Hoon Song
    Department of Integrative Medical Sciences, Northeastern Ohio Universities Colleges of Medicine and Pharmacy, Rootstown, OH 44272, USA
    J Lipid Res 51:2223-33. 2010
    ..Under certain conditions, miRNA may reduce CYP7A1 mRNA stability to inhibit bile acid synthesis, and the miR-122a antagomirs may stimulate bile acid synthesis to reduce serum cholesterol and triglycerides...
  33. pmc A novel bile acid-activated vitamin D receptor signaling in human hepatocytes
    Shuxin Han
    Department of Integrative Medical Sciences, Northeastern Ohio University s Colleges of Medicine and Pharmacy, 4209 State Route 44, Rootstown, Ohio 44272, USA
    Mol Endocrinol 24:1151-64. 2010
    ..This membrane VDR-signaling pathway may be activated by bile acids to inhibit bile acid synthesis as a rapid response to protect hepatocytes from cholestatic liver injury...
  34. pmc Fenofibrate differentially regulates plasminogen activator inhibitor-1 gene expression via adenosine monophosphate-activated protein kinase-dependent induction of orphan nuclear receptor small heterodimer partner
    Dipanjan Chanda
    Hormone Research Center, School of Biological Sciences and Technology, Chonnam National University, Gwangju, Republic of Korea
    Hepatology 50:880-92. 2009
    ..Fenofibrate exhibited a differential inhibitory pattern on PAI-1 gene expression depending on the transcription factors inhibited by SHP...