Download PDF
Horm Metab Res 2011; 43(7): 458-463
DOI: 10.1055/s-0031-1275325
Original Basic

© Georg Thieme Verlag KG Stuttgart · New York

A Novel Mechanism for Decreasing Plasma Lipid Level from Imidazoline I-1 Receptor Activation in High Fat Diet-fed Mice

C-S. Niu1 , H-T. Wu2 , K-C. Cheng3 , K-C. Lin4 , 5 , C-T. Chen4 , [*] , J-T. Cheng2 , 4 , [*]
  • 1Department of Nursing, Tzu Chi College of Technology, Hualien City, Taiwan
  • 2Institute of Basic Medical Sciences, College of Medicine, National Cheng Kung University, Tainan City, Taiwan, R.O.C
  • 3Department of Psychosomatic Internal Medicine, Kagoshima University Graduate School of Medical and Dental Sciences, Kagoshima City, Japan
  • 4Department of Medical Research, Neurology and Pediatrics, Chi-Mei Medical Center, Yong Kang City, Tainan County, Taiwan, R.O.C
  • 5Institute of Biotechnology, Nan-Tai University, Yong Kang City, Tainan County, Taiwan, R.O.C
Further Information

Publication History

received 15.12.2010

accepted 10.03.2011

Publication Date:
11 April 2011 (online)

Also available at
    Permissions and Reprints

Abstract

The imidazoline I-1 receptor (I-1 R) agonists are widely used to lower blood pressure, but their effects on hyperlipidemia are still obscure. The present study is aimed to evaluate the possible mechanism(s) of I-1 R in the regulation of lipid homeostasis. Farnesoid X receptor (FXR) plays an important role in blood lipid homeostasis; however, the role of FXR in rilmenidine-induced blood lipid lowering action is still unknown. Thus, we administered rilmenidine, a selective agonist of I-1 R, into high fat diet-fed (HFD) mice showing hypertriglyceridemia and hypercholesterolemia. Rilmenidine significantly ameliorated hyperlipidemia in HFD mice after 7 days of administration. Pretreatment with efaroxan, at a dose sufficient to inhibit I-1 R activation, blocked the effects of rilmenidine. Also, in cultured HepG2 cells, rilmenidine dose-dependently induced the expression of farnesoid X receptor (FXR). The rilmenidine-induced FXR expression and FXR-related genes were blocked by efaroxan. However, rilmenidine treatment did not affect the expression of enzymes related to β-oxidation. In conclusion, activation of I-1 R may activate FXR to lower plasma lipids, suggesting I-1 R as a new target for the treatment of hyperlipidemia.

Key words

cholesterol - efaroxan - imidazoline receptor - rilmenidine - triglyceride

References

  • 1 Reaven GM. Banting lecture 1988. Role of insulin resistance in human disease.  Diabetes. 1988;  37 1595-1607
    Google Scholar
  • 2 McBride P. Triglycerides and risk for coronary artery disease.  Curr Atheroscler Rep. 2008;  10 386-390
    Google Scholar
  • 3 Howard BV, Ruotolo G, Robbins DC. Obesity and dyslipidemia.  Endocrinol Metab Clin North Am. 2003;  32 855-867
    Google Scholar
  • 4 Bousquet P. Identification and characterization of I1 imidazoline receptors: their role in blood pressure regulation.  Am J Hypertens. 2000;  13 84S-88S
    Google Scholar
  • 5 Ernsberger P, Friedman JE, Koletsky RJ. The I1-imidazoline receptor: from binding site to therapeutic target in cardiovascular disease.  J Hypertens Suppl. 1997;  15 S9-S23
    Google Scholar
  • 6 Velliquette RA, Kossover R, Previs SF, Ernsberger P. Lipid-lowering actions of imidazoline antihypertensive agents in metabolic syndrome X.  Naunyn Schmiedebergs Arch Pharmacol. 2006;  372 300-312
    Google Scholar
  • 7 Lui TN, Tsao CW, Huang SY, Chang CH, Cheng JT. Activation of imidazoline I2B receptors is linked with AMP kinase pathway to increase glucose uptake in cultured C2C12 cells.  Neurosci Lett. 2010;  474 144-147
    Google Scholar
  • 8 Raasch W, Schafer U, Chun J, Dominiak P. Biological significance of agmatine, an endogenous ligand at imidazoline binding sites.  Br J Pharmacol. 2001;  133 755-780
    Google Scholar
  • 9 Lu TT, Repa JJ, Mangelsdorf DJ. Orphan nuclear receptors as eLiXiRs and FiXeRs of sterol metabolism.  J Biol Chem. 2001;  276 37735-37738
    Google Scholar
  • 10 Repa JJ, Mangelsdorf DJ. The liver X receptor gene team: potential new players in atherosclerosis.  Nat Med. 2002;  8 1243-1248
    Google Scholar
  • 11 Claudel T, Staels B, Kuipers F. The Farnesoid X receptor: a molecular link between bile acid and lipid and glucose metabolism.  Arterioscler Thromb Vasc Biol. 2005;  25 2020-2030
    Google Scholar
  • 12 Watanabe M, Houten SM, Wang L, Moschetta A, Mangelsdorf DJ, Heyman RA, Moore DD, Auwerx J. Bile acids lower triglyceride levels via a pathway involving FXR, SHP, and SREBP-1c.  J Clin Invest. 2004;  113 1408-1418
    Google Scholar
  • 13 Beyer TP, Schmidt RJ, Foxworthy P, Zhang Y, Dai J, Bensch WR, Kauffman RF, Gao H, Ryan TP, Jiang XC, Karathanasis SK, Eacho PI, Cao G. Coadministration of a liver X receptor agonist and a peroxisome proliferator activator receptor-alpha agonist in Mice: effects of nuclear receptor interplay on high-density lipoprotein and triglyceride metabolism in vivo.  J Pharmacol Exp Ther. 2004;  309 861-868
    Google Scholar
  • 14 Kane CD, Stevens KA, Fischer JE, Haghpassand M, Royer LJ, Aldinger C, Landschulz KT, Zagouras P, Bagley SW, Hada W, Dullea R, Hayward CM, Francone OL. Molecular characterization of novel and selective peroxisome proliferator-activated receptor alpha agonists with robust hypolipidemic activity in vivo.  Mol Pharmacol. 2009;  75 296-306
    Google Scholar
  • 15 Wang SR, Pessah M, Infante J, Catala D, Salvat C, Infante R. Lipid and lipoprotein metabolism in Hep G2 cells.  Biochim Biophys Acta. 1988;  961 351-363
    Google Scholar
  • 16 Chapados NA, Seelaender M, Levy E, Lavoie JM. Effects of exercise training on hepatic microsomal triglyceride transfer protein content in rats.  Horm Metab Res. 2009;  41 287-393
    Google Scholar
  • 17 Ji W, Gong BQ. Hypolipidemic effects and mechanisms of Panax notoginseng on lipid profile in hyperlipidemic rats.  J Ethnopharmacol. 2007;  113 318-324
    Google Scholar
  • 18 Yu S, Rao S, Reddy JK. Peroxisome proliferator-activated receptors, fatty acid oxidation, steatohepatitis and hepatocarcinogenesis.  Curr Mol Med. 2003;  3 561-572
    Google Scholar
  • 19 Goldwasser J, Cohen PY, Yang E, Balaguer P, Yarmush ML, Nahmias Y. Transcriptional regulation of human and rat hepatic lipid metabolism by the grapefruit flavonoid naringenin: role of PPARalpha, PPARgamma and LXRalpha.  PLoS One. 2010;  5 e12399
    Google Scholar
  • 20 Chen N, Bezzina R, Hinch E, Lewandowski PA, Cameron-Smith D, Mathai ML, Jois M, Sinclair AJ, Begg DP, Wark JD, Weisinger HS, Weisinger RS. Green tea, black tea, and epigallocatechin modify body composition, improve glucose tolerance, and differentially alter metabolic gene expression in rats fed a high-fat diet.  Nutr Res. 2009;  29 784-793
    Google Scholar
  • 21 Song S, Attia RR, Connaughton S, Niesen MI, Ness GC, Elam MB, Hori RT, Cook GA, Park EA. Peroxisome proliferator activated receptor alpha (PPARalpha) and PPAR gamma coactivator (PGC-1alpha) induce carnitine palmitoyltransferase IA (CPT-1A) via independent gene elements.  Mol Cell Endocrinol. 2010;  325 54-63
    Google Scholar
  • 22 Zhang D, Christianson J, Liu ZX, Tian L, Choi CS, Neschen S, Dong J, Wood PA, Shulman GI. Resistance to high-fat diet-induced obesity and insulin resistance in mice with very long-chain acyl-CoA dehydrogenase deficiency.  Cell Metab. 2010;  11 402-411
    Google Scholar
  • 23 Forman BM, Goode E, Chen J, Oro AE, Bradley DJ, Perlmann T, Noonan DJ, Burka LT, McMorris T, Lamph WW, Evans RM, Weinberger C. Identification of a nuclear receptor that is activated by farnesol metabolites.  Cell. 1995;  81 687-693
    Google Scholar
  • 24 Zhang Y, Kast-Woelbern HR, Edwards PA. Natural structural variants of the nuclear receptor farnesoid X receptor affect transcriptional activation.  J Biol Chem. 2003;  278 104-110
    Google Scholar
  • 25 Sinal CJ, Tohkin M, Miyata M, Ward JM, Lambert G, Gonzalez FJ. Targeted disruption of the nuclear receptor FXR/BAR impairs bile acid and lipid homeostasis.  Cell. 2000;  102 731-744
    Google Scholar
  • 26 Edwards PA, Kast HR, Anisfeld AM. BAREing it all: the adoption of LXR and FXR and their roles in lipid homeostasis.  J Lipid Res. 2002;  43 2-12
    Google Scholar
  • 27 Maloney PR, Parks DJ, Haffner CD, Fivush AM, Chandra G, Plunket KD, Creech KL, Moore LB, Wilson JG, Lewis MC, Jones SA, Willson TM. Identification of a chemical tool for the orphan nuclear receptor FXR.  J Med Chem. 2000;  43 2971-2974
    Google Scholar
  • 28 Kast HR, Nguyen CM, Sinal CJ, Jones SA, Laffitte BA, Reue K, Gonzalez FJ, Willson TM, Edwards PA. Farnesoid X-activated receptor induces apolipoprotein C-II transcription: a molecular mechanism linking plasma triglyceride levels to bile acids.  Mol Endocrinol. 2001;  15 1720-1728
    Google Scholar
  • 29 Zhang Y, Castellani LW, Sinal CJ, Gonzalez FJ, Edwards PA. Peroxisome proliferator-activated receptor-gamma coactivator 1alpha (PGC-1alpha) regulates triglyceride metabolism by activation of the nuclear receptor FXR.  Genes Dev. 2004;  18 157-169
    Google Scholar
  • 30 Horton JD, Goldstein JL, Brown MS. SREBPs: activators of the complete program of cholesterol and fatty acid synthesis in the liver.  J Clin Invest. 2002;  109 1125-1131
    Google Scholar
  • 31 Goldberg IJ, Scheraldi CA, Yacoub LK, Saxena U, Bisgaier CL. Lipoprotein ApoC-II activation of lipoprotein lipase. Modulation by apolipoprotein A-IV.  J Biol Chem. 1990;  265 4266-4272
    Google Scholar
  • 32 Staels B, Vu-Dac N, Kosykh VA, Saladin R, Fruchart JC, Dallongeville J, Auwerx J. Fibrates downregulate apolipoprotein C-III expression independent of induction of peroxisomal acyl coenzyme A oxidase. A potential mechanism for the hypolipidemic action of fibrates.  J Clin Invest. 1995;  95 705-712
    Google Scholar
  • 33 Claudel T, Inoue Y, Barbier O, Duran-Sandoval D, Kosykh V, Fruchart J, Fruchart JC, Gonzalez FJ, Staels B. Farnesoid X receptor agonists suppress hepatic apolipoprotein CIII expression.  Gastroenterology. 2003;  125 544-555
    Google Scholar
  • 34 Blacklow SC. Versatility in ligand recognition by LDL receptor family proteins: advances and frontiers.  Curr Opin Struct Biol. 2007;  17 419-426
    Google Scholar
  • 35 Ma PT, Gil G, Südhof TC, Bilheimer DW, Goldstein JL, Brown MS. Mevinolin, an inhibitor of cholesterol synthesis, induces mRNA for low density lipoprotein receptor in livers of hamsters and rabbits.  Proc Natl Acad Sci U S A. 1986;  83 8370-8374
    Google Scholar
  • 36 Bilheimer DW, Grundy SM, Brown MS, Goldstein JL. Mevinolin and colestipol stimulate receptor-mediated clearance of low density lipoprotein from plasma in familial hypercholesterolemia heterozygotes.  Proc Natl Acad Sci USA. 1983;  80 4124-4128
    Google Scholar
  • 37 Cayla C, Schaak S, Roquelaine C, Gales C, Quinchon F, Paris H. Homologous regulation of the alpha2C-adrenoceptor subtype in human hepatocarcinoma, HepG2.  Br J Pharmacol. 1999;  126 69-78
    Google Scholar
  • 38 Charlton-Menys V, Durrington PN. Human cholesterol metabolism and therapeutic molecules.  Exp Physiol. 2008;  93 27-42
    Google Scholar

1 These authors contributed equally to this work.

Correspondence

Prof. J-T. Cheng

Institute of Basic Medical

Sciences

College of Medicine

National Cheng Kung University

Tainan City

Taiwan 70101

R.O.C

Phone: +886/6/331 8516

Fax: +886/6/331 7532

Prof. C-T. Chen

Department of Pediatrics

Chi-Mei Medical Center

Tainan City

Taiwan 73101

R.O.C

Phone: +886/6/251 7864

Fax: +886/6/253 2639

Email: jtcheng@mail.ncku.edu.tw

      >