Skip to main content
SpringerLink
Log in

Peroxisome proliferator-activated receptor-α selective ligand reduces adiposity, improves insulin sensitivity and inhibits atherosclerosis in LDL receptor-deficient mice

  • Published:
Molecular and Cellular Biochemistry Aims and scope Submit manuscript

Abstract

Fenofibrate, a selective 1PPAR-α activator, is prescribed to treat human dyslipidemia. The aim of this study was to delineate the mechanism of fenofibrate-mediated reductions in adiposity, improvements in insulin sensitivity, and lowering of triglycerides (TG) and free fatty acids (FFA) and to investigate if these favorable changes are related to the inhibition of lipid deposition in the aorta. To test this hypothesis we used male LDLr deficient mice that exhibit the clinical features of metabolic syndrome X when fed a high fat high cholesterol (HF) diet. LDLr deficient mice fed HF diet and simultaneously treated with fenofibrate (100 mg/kg body weight) prevented development of obesity, lowered serum triglycerides and cholesterol, improved insulin sensitivity, and prevented accumulation of lipids in the aorta. Lowering of circulating lipids occurred via down-regulation of lipogenic genes, including fatty acid synthase, acetyl CoA carboxylase and diacyl glycerol acyl transferase-2, concomitant with decreased liver TG and cholesterol, and TG output rate. Fenofibrate also suppressed liver apoCIII mRNA levels and markedly increased lipoprotein lipase mRNA levels, known to enhance serum TG catabolism. In addition, fenofibrate profoundly reduced epididymal fat and mesenteric fat mass to the levels seen in lean mice. The reductions in body weight were associated with elevation of hepatic uncoupling protein 2 (UCP2) mRNA, a concomitant increase in the ketone body formation, and improved insulin sensitivity associated with tumor necrosis factor-α reductions and phosphoenol pyruvate carboxykinase down-regulation. These results demonstrate that fenofibrate improves lipid abnormalities partly via inhibition of TG production and partly via clearance of TG-rich apoB particles by elevating LPL and reduced apoCIII. The prevention of obesity development occurred via energy expenditure. Fenofibrate-mediated hypolipidemic effects together with improved insulin sensitivity and loss of adiposity led to the reductions in the aortic lipid deposition by inhibiting early stages of atherosclerosis possibly via vascular cell adhesion molecule-1 (VCAM-1) modulation. These results suggest that potent PPAR-α activators may be useful in the treatment of syndrome X. (Mol Cell Biochem xxx: 1–16, 2005)

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

Abbreviations

PPAR:

Peroxisome proliferator activated receptor

LDLr:

low density lipoprotein receptor

SREBP1:

Sterol response element binding protein 1

DGAT2:

Diacyl glycerol acyl transferase

PEPCK:

Phosphoenol pyruvate carboxy kinase

TNF-α:

Tumor necrosis factor alpha

UCP:

Uncoupling protein

LPL:

Lipoprotein lipase

ACO:

Acetyl CoA oxidase

ACC:

Acetyl CoA carboxylase

FAS:

Fatty acid synthase

VCAM1:

Vascular cell adhesion molecule 1

HAEC:

Human aortic endothelial cell

References

  1. Moller DE, Kaufman KD: Metabolic syndrome: A clinical and molecular perspective. Annual Review of Medicine 56: 45–62, 2005

    Article  PubMed  CAS  Google Scholar 

  2. Reaven GM: Pathophysiology of insulin resistance in human disease. Physiol Rev 75: 473–486, 1995

    PubMed  CAS  Google Scholar 

  3. Srivastava RAK Srivastava N: Search for obesity drugs: targeting central and peripheral pathways. Curr Med Chem- Immunol, Endo & Met Ag 4: 75–90, 2004

    Article  Google Scholar 

  4. Szapary PO, Rader DJ: The triglyceride-high-density lipoprotein axis: an important target of therapy? Am Heart J 148: 211–221, 2004

    Article  PubMed  CAS  Google Scholar 

  5. Sowers JR, Epstein M, Frohlich ED: Diabetes, hypertension, and cardiovascular disease: an update. Hypertension 37: 1053–1059, 2001

    Google Scholar 

  6. Norhammar A, Malmberg K, Diderholm E, Lagerqvist B, Lindahl B, Ryden L, Wallentin L: Diabetes mellitus: the major risk factor in unstable coronary artery disease even after consideration of the extent of coronary artery disease and benefits of revascularization. J Am Coll Cardiol 43(4): 585–591, 2004

    Google Scholar 

  7. Candido R, Srivastava P, Cooper ME, Burrell LM: Diabetes mellitus: a cardiovascular disease. Curr Opin Investig Drugs 4: 1088–1094, 2003

    PubMed  Google Scholar 

  8. Rubins HB: Triglycerides and coronary heart disease: implications of recent clinical trials. J Cardiovasc Risk 7: 339–345, 2000 (Review)

    Google Scholar 

  9. George Steiner and Diabetes Atherosclerosis Intervention Study Investigators. Effect of fenofibrate on progression of coronary-artery disease in type 2 diabetes: the Diabetes Atherosclerosis Intervention Study, a randomised study. Lancet 357: 905–910, 2001

    Google Scholar 

  10. Krentz AJ: Lipoprotein abnormalities and their consequences for patients with type 2 diabetes. Diabetes Obes Metab Suppl 1: S19–27, 2003

    Article  Google Scholar 

  11. Reaven G, Abbasi F, McLaughlin T: Obesity, insulin resistance, and cardiovascular disease. Recent Prog Horm Res 59: 207–223, 2004 (Review)

    Google Scholar 

  12. Kotani K, Peroni OD, Minokoshi Y, Boss O, Kahn BB: GLUT4 glucose transporter deficiency increases hepatic lipid production and peripheral lipid utilization. J Clin Invest 114: 1666–1675, 2004

    Article  PubMed  CAS  Google Scholar 

  13. Adeli K, Taghibiglou C, Van Iderstine SC, Lewis GF: Mechanisms of hepatic very low-density lipoprotein overproduction in insulin resistance. Trends Cardiovasc Med 11: 170–176, 2001 (Review)

    Google Scholar 

  14. Taghibiglou C, Carpentier A, Van Iderstine SC, Chen B, Rudy D, Aiton A, Lewis GF, Adeli K: Mechanisms of hepatic very low density lipoprotein overproduction in insulin resistance. Evidence for enhanced lipoprotein assembly, reduced intracellular ApoB degradation, and increased microsomal triglyceride transfer protein in a fructose-fed hamster model. J Biol Chem 275: 8416–8425, 2000

    Article  PubMed  CAS  Google Scholar 

  15. Fazio S, Linton MF: The role of fibrates in managing hyperlipidemia: mechanisms of action and clinical efficacy. Curr Atheroscler Rep 6: 148–157, 2004 (Review)

    Google Scholar 

  16. Duez H, Lefebvre B, Poulain P, Pineda Torra I, Percevault F, Luc G, Peters JM, Gonzalez FJ, Gineste R, Helleboid S, Fruchart JC, Fievet C, Lefebvre P, Staels B: Regulation of human ApoA-I by gemfibrozil and fenofibrate through selective peroxisome proliferator-activated receptor α modulation. Arterioscler Thromb Vasc Biol 225: 585–591, 2004

    Google Scholar 

  17. Huang B, Wu P, Bowker-Kinley MM, Harris RA: Regulation of pyruvate dehydrogenase kinase expression by peroxisome proliferator-activated receptor-alpha ligands, glucocorticoids, and insulin. Diabetes 51: 276–283, 2002

    PubMed  CAS  Google Scholar 

  18. Frederiksen KS, Wulff EM, Sauerberg P, Mogensen JP, Jeppesen L, Fleckner J: Prediction of PPAR-alpha ligand-mediated physiological changes using gene expression profiles. J Lipid Res 45: 592–601, 2004

    Article  PubMed  CAS  Google Scholar 

  19. Son C, Hosoda K, Matsuda J, Fujikura J, Yonemitsu S, Iwakura H, Masuzaki H, Ogawa Y, Hayashi T, Itoh H, Nishimura H, Inoue G, Yoshimasa Y, Yamori Y, Nakao K: Up-regulation of uncoupling protein 3 gene expression by fatty acids and agonists for PPARs in L6 myotubes. Endocrinology 142: 4189–4194, 2001

    Article  PubMed  CAS  Google Scholar 

  20. Frederiksen KS, Wulff EM, Sauerberg P, Mogensen JP, Jeppesen L, Fleckner J: Differential influences of peroxisome proliferator-activated receptors gamma and -alpha on food intake and energy homeostasis. Diabetes 52: 2249–2259, 2003

    Google Scholar 

  21. Guerre-Millo M, Gervois P, Raspe E, Madsen L, Poulain P, Derudas B, Herbert JM, Winegar DA, Willson TM, Fruchart JC, Berge RK, Staels B: Peroxisome proliferator-activated receptor alpha activators improve insulin sensitivity and reduce adiposity. J Biol Chem 275: 16638–16642, 2000

    Article  PubMed  CAS  Google Scholar 

  22. Guerre-Millo M, Rouault C, Poulain P, Andre J, Poitout V, Peters JM, Gonzalez FJ, Fruchart JC, Reach G, Staels B: PPAR-alpha-null mice are protected from high-fat diet-induced insulin resistance. Diabetes 50: 2809–2814, 2001

    PubMed  CAS  Google Scholar 

  23. Li AC, Brown KK, Silvestre MJ, Willson TM, Palinski W, Glass CK: Peroxisome proliferator-activated receptor gamma ligands inhibit development of atherosclerosis in LDL receptor-deficient mice. J Clin Invest 106: 523–531, 2000

    PubMed  CAS  Google Scholar 

  24. Jeong S, Kim M, Han M, Lee H, Ahn J, Kim M, Song YH, Shin C, Nam KH, Kim TW, Oh GT, Yoon M: Fenofibrate prevents obesity and hypertriglyceridemia in low-density lipoprotein receptor-null mice. Metabolism 53: 607–613, 2004

    Article  PubMed  CAS  Google Scholar 

  25. Aalto-Setala K, Fisher EA, Chen X, Chajek-Shaul T, Hayek T, Zechner R, Walsh A, Ramakrishnan R, Ginsberg HN, Breslow JL: Mechanism of hypertriglyceridemia in human apolipoprotein (apo) CIII transgenic mice. Diminished very low density lipoprotein fractional catabolic rate associated with increased apo CIII and reduced apo E on the particles. J Clin Invest 90(5): 1889–1900, 1992

    Google Scholar 

  26. Haubenwallner S, Essenburg AD, Barnett BC, Pape ME, DeMattos RB, Krause BR, Minton LL, Auerbach BJ, Newton RS, Leff T, et al.: Hypolipidemic activity of select fibrates correlates to changes in hepatic apolipoprotein C-III expression: a potential physiologic basis for their mode of action. J Lipid Res 36: 2541–2551, 1995

    PubMed  CAS  Google Scholar 

  27. Frenkel B, Bishara-Shieban J, Bar-Tana J: The effect of beta,beta′-tetramethylhexadecane-dioic acid (MEDICA 16) on plasma very-low-density lipoprotein metabolism in rats: role of apolipoprotein C-III. Biochem J 298: 409–414, 1994

    PubMed  CAS  Google Scholar 

  28. Bisgaier CL, Essenburg AD, Barnett BC, Auerbach BJ, Haubenwallner S, Leff T, White AD, Creger P, Pape ME, Rea TJ, Newton RS: A novel compound that elevates high density lipoprotein and activates the peroxisome proliferator activated receptor. J Lipid Res 39: 17–30, 1998. Erratum in: J Lipid Res 39: 1317, 1998

    Google Scholar 

  29. Srivastava RAK, Jiao S, Tang J, Pfleger B, Kitchens T, Schonfeld G: In vivo regulation of LDL receptor and apoB gene expressions in inbred strains of mice by dietary fatty acids and cholesterol. Biochim Biophys Acta 1086: 29–43, 1991

    PubMed  CAS  Google Scholar 

  30. Srivastava RAK, Tang J, Krul ES, Pfleger B, Kitchens RT, Schonfeld G: Dietary fatty acids and cholesterol differ in their effects on the in vivo regulation of apoAI and apoAII gene expressions in inbred strains of mice. Biochim Biophys Acta 1125: 251–261, 1992

    PubMed  CAS  Google Scholar 

  31. Ojeda MO, van't Veer C, Fernandez Ortega CB, Arana Rosainz Mde J, Buurman WA: Inflamm Res 54: 74–81, 2005

    Google Scholar 

  32. Srivastava RAK, Toth L, Srivastava N, Maeda N, Schonfeld G: Regulation of the apolipoprotein B in heterozygous hypobetalipoproteinemic knock-out mice expressing truncated apoB, B81. Low production and enhanced clearance of apoB cause low levels of apoB. Mol Cell Biochem 202: 37–46, 1999

    Article  PubMed  CAS  Google Scholar 

  33. Srivastava RAK: Analysis of RNA by Northern blotting using riboprobes. Methods in Molecular Biology 86: 103–112, 1998

    PubMed  CAS  Google Scholar 

  34. Srivastava RAK, Srivastava N, Maurizio A, Lin RC, Korach K, Lubahn D, Schonfeld G: Regulation of apolipoprotein E gene expression by estrogen occurs by translational mechanism via estrogen receptor mediated pathway. J Biol Chem 272: 33360–33366, 1997

    Article  PubMed  CAS  Google Scholar 

  35. Zhang WJ, Frei B: Albumin selectively inhibits TNF alpha-induced expression of vascular cell adhesion molecule-1 in human aortic endothelial cells. Cardiovasc Res 55: 820–829, 2002

    Article  PubMed  CAS  Google Scholar 

  36. Kramer D, Shapiro R, Adler A, Bush E, Rondinone CM: Insulin-sensitizing effect of rosiglitazone (BRL-49653) by regulation of glucose transporters in muscle and fat of Zucker rats. Metabolism 200150: 1294–1300, 2001

    Article  Google Scholar 

  37. Werner AL: Travaglini MTA review of rosiglitazone in type 2 diabetes mellitus. Pharmacotherapy 21: 1082–99, 2001 (Review)

    Google Scholar 

  38. Miyake JH, Wang SL, Davis RA: Bile acid induction of cytokine expression by macrophages correlates with repression of hepatic cholesterol 7alpha-hydroxylas e, J Biol Chem 275: 21805–21808, 2000

    Article  PubMed  CAS  Google Scholar 

  39. Choi JS, Choi YJ, Park SH, Kang JS, Kang YH: Flavones mitigate tumor necrosis factor-alpha-induced adhesion molecule upregulation in cultured human endothelial cells: role of nuclear factor-kappa B. J Nutr 134: 1013–1019, 2004

    PubMed  CAS  Google Scholar 

  40. Urizar NL, Liverman AB, Dodds DT, Silva FV, Ordentlich P, Yan Y, Gonzalez FJ, Heyman RA, Mangelsdorf DJ, Moore DD: A natural product that lowers cholesterol as an antagonist ligand for FXR. Science 296: 1703–1706, 2002

    Article  PubMed  CAS  Google Scholar 

  41. Schreyer SA, Vick C, Lystig TC, Mystkowski P, LeBoeuf RC: LDL receptor but not apolipoprotein E deficiency increases diet-induced obesity and diabetes in mice. Am J Physiol 282: E207–E214, 2002

    CAS  Google Scholar 

  42. Schreyer SA, Lystig TC, Vick CM, LeBoeuf RC: Mice deficient in apolipoprotein E but not LDL receptors are resistant to accelerated atherosclerosis associated with obesity. Atherosclerosis 171: 49–55, 2003

    Article  PubMed  CAS  Google Scholar 

  43. Duez H, Chao YS, Hernandez M, Torpier G, Poulain P, Mundt S, Mallat Z, Teissier E, Burton CA, Tedgui A, Fruchart JC, Fievet C, Wright SD, Staels B: Reduction of atherosclerosis by the peroxisome proliferator-activated receptor alpha agonist fenofibrate in mice. J Biol Chem 277: 48051–48057, 2002

    Article  PubMed  CAS  Google Scholar 

  44. Mancini FP, Lanni A, Sabatino L, Moreno M, Giannino A, Contaldo F, Colantuoni V, Goglia F: Fenofibrate prevents and reduces body weight gain and adiposity in diet-induced obese rats. FEBS Lett 491: 154–158, 2001

    Article  PubMed  CAS  Google Scholar 

  45. Schwartz S, Raskin P, Fonseca V, Graveline JF: Effect of troglitazone in insulin-treated patients with type II diabetes mellitus. Troglitazone and Exogenous Insulin Study Group. (1998) N Eng J Med 338: 861–866, 1998

    Google Scholar 

  46. Linden D, Lindberg K, Oscarsson J, Claesson C, Asp L, Li L, Gustafsson M, Boren J, Olofsson SO: Influence of peroxisome proliferator-activated receptor alpha agonists on the intracellular turnover and secretion of apolipoprotein (Apo) B-100 and ApoB-48. J Biol Chem 277: 23044–23053, 202, 2002

    Google Scholar 

  47. Frederiksen KS, Wulf EM, Wassermann K, Sauerberg P, Fleckner J: Identification of hepatic transcriptional changes in insulin-resistant rats treated with peroxisome proliferator activated receptor-alpha agonists. J Mol Endocrinol 30: 317–329, 2003

    Article  PubMed  CAS  Google Scholar 

  48. Goudriaan JR, Espirito Santo SM, Voshol PJ, Teusink B, van Dijk KW, van Vlijmen BJ, Romijn JA, Havekes LM, Rensen PC: The VLDL receptor plays a major role in chylomicron metabolism by enhancing LPL-mediated triglyceride hydrolysis. J Lipid Res 45: 1475–1481, 2004

    Article  PubMed  CAS  Google Scholar 

  49. Cases S, Stone SJ, Zhou P, Yen E, Tow B, Lardizabal KD, Voelker T, Farese RV, Jr: Cloning of DGAT2, a second mammalian diacylglycerol acyltransferase, and related family members. J Biol Chem 276: 38870–38876, 2001

    Article  PubMed  CAS  Google Scholar 

  50. Goodpaster BH, Kelley DE: Role of muscle in triglyceride metabolism. Curr Opin Lipidol 9: 231–236, 1998

    Article  PubMed  CAS  Google Scholar 

  51. Ye JM, Doyle PJ, Iglesias MA, Watson DG, Cooney GJ, Kraegen EW: Peroxisome proliferator-activated receptor (PPAR)-alpha activation lowers muscle lipids and improves insulin sensitivity in high fat-fed rats: comparison with PPAR-gamma activation. Diabetes 50: 411–417, 2001

    PubMed  CAS  Google Scholar 

  52. Hotamisligil GS, Arner P, Caro JF, Atkinson RL, Spiegelman BM: Increased adipose tissue expression of tumor necrosis factor-alpha in human obesity and insulin resistance. J Clin Invest 95: 2409–2415, 1995

    PubMed  CAS  Google Scholar 

  53. Hotamisligil GS, Shargill NS, Spiegelman BM: Adipose expression of tumor necrosis factor-alpha: direct role in obesity-linked insulin resistance. Science 59: 87–91, 1993

    Google Scholar 

  54. Staels B, Koenig W, Habib A, Merval R, Lebret M, Pineda Torra I, Delerive P, Fadel A, Chinetti G, Fruchart J -C, Najib J, Maclouf J, Tedgui A: Activation of human aortic smooth-muscle cells is inhibited by PPARalpha but not by PPARgamma activators. Nature 393: 790–793, 1998

    Article  PubMed  CAS  Google Scholar 

  55. Fu T, Kashireddy P, Borensztajn J: The peroxisome-proliferator-activated receptor alpha agonist ciprofibrate severely aggravates hypercholesterolaemia and accelerates the development of atherosclerosis in mice lacking apolipoprotein E. Biochem J 373: 941–947, 2003

    Article  PubMed  CAS  Google Scholar 

  56. Li AC, Binder CJ, Gutierrez A, Brown KK, Plotkin CR, Pattison JW, Valledor AF, Davis RA, Willson TM, Witztum JL, Palinski W, Glass CK: Differential inhibition of macrophage foam-cell formation and atherosclerosis in mice by PPARalpha, beta/delta, and gamma. J Clin Invest 114: 1564–1576, 2004

    Article  PubMed  CAS  Google Scholar 

  57. Branen L, Havgaard L, Nitulescu M, Bengtsson E, Nilsson J, Jovinge S: Inhibition of tumor necrosis factor-alpha reduces atherosclerosis in apolipoprotein E knockout mice. Arterioscl Thromb Vasc Biol 24: 2137–2142, 2004

    Article  PubMed  CAS  Google Scholar 

  58. Cybulsky MI, Iiyama K, Li H, Zhu S, Chen M, IIyama M, Davis V, Gutrerrez-Ramos J, Connelly PW, Milstone DS: A major role for VCAM-1, but not ICAM-1, in early atherosclerosis. J Clin Invest 107: 1255–1262, 2001

    Article  PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. CloneGen Biotechnology, Ann Arbor, MI, USA

    Rai Ajit K. Srivastava & Ravi Jahagirdar

  2. Stanford University School of Medicine, Palo Alto, CA, USA

    Salman Azhar

  3. Nicholas Piramal Research Center, Mumbai, India

    Somesh Sharma

  4. Esperion Therapeutics, A Division of Pfizer Global Research & Development, Ann Arbor, MI, USA

    Charles L. Bisgaier

  5. Department of Atherosclerosis, Bristol-Myers Squibb, Pennington, NJ, USA

    Rai Ajit K. Srivastava

Authors
  1. Rai Ajit K. Srivastava
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Ravi Jahagirdar
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Salman Azhar
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Somesh Sharma
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Charles L. Bisgaier
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Rai Ajit K. Srivastava.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Srivastava, R.A.K., Jahagirdar, R., Azhar, S. et al. Peroxisome proliferator-activated receptor-α selective ligand reduces adiposity, improves insulin sensitivity and inhibits atherosclerosis in LDL receptor-deficient mice. Mol Cell Biochem 285, 35–50 (2006). https://doi.org/10.1007/s11010-005-9053-y

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11010-005-9053-y

Keywords

Search

Navigation