Regulation of Hepatic SphK2 by Bile Acids: Effects on Lipid Metabolism

Summary

Principal Investigator: HUIPING ROSE ZHOU
Abstract: DESCRIPTION (provided by applicant): Bile acids are crucial for lipid homeostasis in the liver. During the last decade, researchers have discovered that bile acids not only act as detergents, but also as important signaling molecules. They have been shown to regulate the expression of numerous genes encoding enzymes/proteins involved in the metabolism/synthesis of bile acids, glucose, fatty acids, and lipoproteins as well as energy metabolism by activating specific nuclear receptors, a G protein coupled receptor (GPCR, TGR5), and multiple signaling pathways in cells of the liver and gastrointestinal tract. We have previously reported that conjugated bile acids activate the AKT and ERK1/2 pathways via G[unreadable]i protein coupled receptor(s). Our most recent studies show that bile acids upregulate sphingosine kinase 2 (SphK2) expression (at both mRNA and protein levels) and enzyme activity and increase serum sphingosine-1-phosphate (S1P) levels. Activation of SphK2 by ERK1/2 increases nuclear S1P levels, which has been shown to be an inhibitor of specific histone deacetylases (HDAC 1 and 2). Increased histone acetylation is often associated with an increase in the transcriptional activity of physiologically linked genes. Our preliminary data strongly indicates that conjugated bile acids along with S1P activate the S1P receptor 2 (S1P2), which further activates the downstream ERK1/2 and AKT signaling pathways in hepatocytes. We recently discovered that in SphK2-/- mice the mRNA levels of key transcriptional factors and key enzymes involved in hepatic lipid metabolism were significantly down-regulated. The SphK2-/- mouse was also found to have an ~18-fold increase in serum triglycerides and a 2 to 5-fold decrease in both HDL and LDL as compared to wild-type control mice. Moreover, tauroursodeoxycholate (TUDCA)-mediated inhibition of lipid accumulation was reversed in the primary hepatocytes of S1P2-/- and SphK2-/- mice. However, the physiological link between bile acids, S1P, S1P receptors and their roles in regulating hepatic sterol/lipid metabolism have not been revealed. Based on the recent studies and our preliminary results, we hypothesize that bile acid-mediated activation of S1P2 plays a critical role in regulating hepatic lipid metabolism by phosphorylation and activation of SphK2 in the nucleus. The following three specific aims are proposed to test our central hypothesis. Aim 1: Characterize the activation of S1P2 by different bile acids and determine the structural-functional relationship of S1P2 and bile acids;Aim 2: Elucidate the role of S1P2 and SphK2 in bile acid-mediated regulation of hepatic sterol/lipid metabolism using S1P2-/- and SphK2-/- mice models;Aim 3: Determine the effects of administration of different bile acids (TUDCA, glycocholate and deoxycholate) and S1P2 antagonist on SphK2 expression and activity as well as activities of HDAC1 and HDAC2 in the liver using an in vivo rat model of bile acid depletion. Completion of this study will not only establish a novel theory in bile acid biology, but will also provide new mechanistic insights into the pathophysiology of dyslipidemia and other metabolic diseases including non-alcoholic fatty liver disease (NAFLD). Also, this study has potential impact on the identification and development of novel therapeutic targets for effective treatment of NAFLD and other related metabolic diseases.
Funding Period: 2000-04-01 - 2016-03-31
more information: NIH RePORT

Top Publications

  1. ncbi Human chorionic gonadotropin modulates prostate cancer cell survival after irradiation or HMG CoA reductase inhibitor treatment
    Adly Yacoub
    Department of Biochemistry, 401 College St, Massey Cancer Center, Room 2 108, Box 980035, Virginia Commonwealth University, Richmond VA 23298 0035, USA
    Mol Pharmacol 71:259-75. 2007
  2. ncbi Conjugated bile acids promote cholangiocarcinoma cell invasive growth through activation of sphingosine 1-phosphate receptor 2
    Runping Liu
    Department of Microbiology and Immunology, School of Medicine, Virginia Commonwealth University, Richmond, VA Key Laboratory of New Drug Screen and Drug Metabolism and Pharmacokinetics, China Pharmaceutical University, Nanjing, China
    Hepatology 60:908-18. 2014
  3. pmc Conjugated bile acids activate the sphingosine-1-phosphate receptor 2 in primary rodent hepatocytes
    Elaine Studer
    Microbiology and Immunology, Virginia Commonwealth University, Richmond, VA 23298 0678, USA
    Hepatology 55:267-76. 2012
  4. pmc Bile acids regulate hepatic gluconeogenic genes and farnesoid X receptor via G(alpha)i-protein-coupled receptors and the AKT pathway
    Risheng Cao
    Departments of Microbiology and Immunology, Virginia Commonwealth University, Richmond, VA 23298, USA
    J Lipid Res 51:2234-44. 2010
  5. pmc Bile acids as regulatory molecules
    Phillip B Hylemon
    Department of Microbiology and Immunology, Medical College of Virginia Campus, Virginia Commonwealth University, Richmond, VA 23298 0678, USA
    J Lipid Res 50:1509-20. 2009
  6. pmc Regulation of autophagy by ceramide-CD95-PERK signaling
    Margaret A Park
    Department of Biochemistry, Virginia Commonwealth University, Richmond, Virginia 23298 0035, USA
    Autophagy 4:929-31. 2008
  7. pmc Clostridium scindens baiCD and baiH genes encode stereo-specific 7alpha/7beta-hydroxy-3-oxo-delta4-cholenoic acid oxidoreductases
    Dae Joong Kang
    Department of Microbiology and Immunology, Medical College of Virginia Campus, Virginia Commonwealth University, Richmond, VA 23298, USA
    Biochim Biophys Acta 1781:16-25. 2008
  8. pmc Activation of bile acid biosynthesis by the p38 mitogen-activated protein kinase (MAPK): hepatocyte nuclear factor-4alpha phosphorylation by the p38 MAPK is required for cholesterol 7alpha-hydroxylase expression
    Zhumei Xu
    Department of Biochemistry and Molecular Biology, Microbiology, Medical College of Virginia at Virginia Commonwealth University, Richmond, Virginia 23298 0614, USA
    J Biol Chem 282:24607-14. 2007
  9. pmc Conjugated bile acids regulate hepatocyte glycogen synthase activity in vitro and in vivo via Galphai signaling
    Youwen Fang
    Department of Biochemistry, Box 980035, Virginia Commonwealth University, Richmond VA 23298 0035, USA
    Mol Pharmacol 71:1122-8. 2007
  10. pmc Bile acids are nutrient signaling hormones
    Huiping Zhou
    Department of Microbiology and Immunology, Virginia Commonwealth University, Medical College of Virginia Campus, Richmond, VA 23298, United States McGuire VA Medical Center, Richmond, VA 23249, United States Electronic address
    Steroids 86:62-8. 2014

Detail Information

Publications10

  1. ncbi Human chorionic gonadotropin modulates prostate cancer cell survival after irradiation or HMG CoA reductase inhibitor treatment
    Adly Yacoub
    Department of Biochemistry, 401 College St, Massey Cancer Center, Room 2 108, Box 980035, Virginia Commonwealth University, Richmond VA 23298 0035, USA
    Mol Pharmacol 71:259-75. 2007
    ..Thus, hCG, in combination with radiation and lovastatin, may represent a novel approach to kill prostate cancer cells...
  2. ncbi Conjugated bile acids promote cholangiocarcinoma cell invasive growth through activation of sphingosine 1-phosphate receptor 2
    Runping Liu
    Department of Microbiology and Immunology, School of Medicine, Virginia Commonwealth University, Richmond, VA Key Laboratory of New Drug Screen and Drug Metabolism and Pharmacokinetics, China Pharmaceutical University, Nanjing, China
    Hepatology 60:908-18. 2014
    ..In a novel organotypic rat CCA coculture model, TCA was further found to significantly increase the growth of CCA cell spheroidal/"duct-like" structures, which was blocked by treatment with JTE-013...
  3. pmc Conjugated bile acids activate the sphingosine-1-phosphate receptor 2 in primary rodent hepatocytes
    Elaine Studer
    Microbiology and Immunology, Virginia Commonwealth University, Richmond, VA 23298 0678, USA
    Hepatology 55:267-76. 2012
    ..In summary, all these data support the hypothesis that conjugated bile acids activate the ERK1/2 and AKT signaling pathways primarily through S1P(2) in primary rodent hepatocytes...
  4. pmc Bile acids regulate hepatic gluconeogenic genes and farnesoid X receptor via G(alpha)i-protein-coupled receptors and the AKT pathway
    Risheng Cao
    Departments of Microbiology and Immunology, Virginia Commonwealth University, Richmond, VA 23298, USA
    J Lipid Res 51:2234-44. 2010
    ..Activation of the insulin signaling pathway appears to be linked to the upregulation of farnesoid X receptor functional activity and SHP induction...
  5. pmc Bile acids as regulatory molecules
    Phillip B Hylemon
    Department of Microbiology and Immunology, Medical College of Virginia Campus, Virginia Commonwealth University, Richmond, VA 23298 0678, USA
    J Lipid Res 50:1509-20. 2009
    ..In this review, we will summarize the current knowledge of how bile acids regulate hepatic lipid and glucose metabolism through the activation of specific nuclear receptors and cell signaling pathways...
  6. pmc Regulation of autophagy by ceramide-CD95-PERK signaling
    Margaret A Park
    Department of Biochemistry, Virginia Commonwealth University, Richmond, Virginia 23298 0035, USA
    Autophagy 4:929-31. 2008
    ..Finally, death receptor induced apoptosis and autophagy could be potential targets for therapeutic intervention...
  7. pmc Clostridium scindens baiCD and baiH genes encode stereo-specific 7alpha/7beta-hydroxy-3-oxo-delta4-cholenoic acid oxidoreductases
    Dae Joong Kang
    Department of Microbiology and Immunology, Medical College of Virginia Campus, Virginia Commonwealth University, Richmond, VA 23298, USA
    Biochim Biophys Acta 1781:16-25. 2008
    ..We tested this hypothesis using cell extracts prepared from E. coli overexpressing the baiCD gene and discovered that it encodes a stereo-specific NAD(H)-dependent 7alpha-hydroxy-3-oxo-Delta4-cholenoic acid oxidoreductase...
  8. pmc Activation of bile acid biosynthesis by the p38 mitogen-activated protein kinase (MAPK): hepatocyte nuclear factor-4alpha phosphorylation by the p38 MAPK is required for cholesterol 7alpha-hydroxylase expression
    Zhumei Xu
    Department of Biochemistry and Molecular Biology, Microbiology, Medical College of Virginia at Virginia Commonwealth University, Richmond, Virginia 23298 0614, USA
    J Biol Chem 282:24607-14. 2007
    ..These studies show a functional link between the p38 signaling pathway, HNF-4alpha, and bile acid synthesis...
  9. pmc Conjugated bile acids regulate hepatocyte glycogen synthase activity in vitro and in vivo via Galphai signaling
    Youwen Fang
    Department of Biochemistry, Box 980035, Virginia Commonwealth University, Richmond VA 23298 0035, USA
    Mol Pharmacol 71:1122-8. 2007
    ....
  10. pmc Bile acids are nutrient signaling hormones
    Huiping Zhou
    Department of Microbiology and Immunology, Virginia Commonwealth University, Medical College of Virginia Campus, Richmond, VA 23298, United States McGuire VA Medical Center, Richmond, VA 23249, United States Electronic address
    Steroids 86:62-8. 2014
    ..The disruption of these signaling pathways may increase the risk of fatty liver and non-alcoholic fatty liver disease (NAFLD). Finally, conjugated bile acids appear to promote cholangiocarcinoma growth via the activation of S1PR2. ..

Research Grants30

  1. The Center for Native and Pacific Health Disparities Research
    MARJORIE K LEIMOMI MALA MAU; Fiscal Year: 2013
    ..5) To prepare and empower our diverse Native and Pacific People communities to take ownership of their own health and wellness. ..
  2. Lipid Transport, Bile Acid Synthesis, and Cholesterol Homeostasis
    William M Pandak; Fiscal Year: 2013
    ..A better understanding of cell cholesterol, fatty acid, and bile acid metabolism is crucial in order to develop more effective therapies for lipid related disorders. ..
  3. CELLULAR AND MOLECULAR BIOLOGY OF LIPOPROTEIN METABOLISM
    Michael C Phillips; Fiscal Year: 2013
    ..The reasons for this protective effect are not understood fully and this project seeks to uncover the molecular mechanisms underlying the beneficial properties of HDL. ..
  4. A Novel Cellular Mechanism for Reducing Hyperlipidemia
    Jingwen Liu; Fiscal Year: 2013
    ....
  5. Mechanism and inhibition of SREBP-dependent cholesterol/lipid metabolism
    Gerhard Wagner; Fiscal Year: 2013
    ..Specific Aim 3: Functionally characterize identified SREBP/co-activator inhibitors using both cell culture and mouse models. ..
  6. Hypo-Lipidemic Actions of Creosote Bush-Derived NDGA
    Salman Azhar; Fiscal Year: 2013
    ....
  7. LIPIN 1 IN THE REGULATION OF HEPATIC LIPID METABOLISM
    Brian N Finck; Fiscal Year: 2013
    ..The results f these studies will not only have implications for our understanding of the biology of lipin proteins, but will also provide new insight into the basic molecular regulation of intermediary metabolism. ..
  8. Role of GDNF in the regulation of hepatic steatosis
    SHANTHI K SRINIVASAN; Fiscal Year: 2013
    ..Identification of new therapies for hepatic steatosis will directly benefit the veteran population. Taken together our data from this proposal may provide novel targets for the treatment or prevention of hepatic steatosis. ..