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Anti-hyperlipidemic and insulin sensitizing activities of fenofibrate reduces aortic lipid deposition in hyperlipidemic Golden Syrian hamster

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Abstract

Cholesterol ester transfer protein (CETP) and apolipoprotein (apo) E are important in peroxisome proliferation activated receptor-α (PPAR-α)-mediated regulation of lipoprotein metabolism. Therefore, popularly used apolipoprotein E knockout mice are not suitable to evaluate PPAR-α agonists. In this study, we aimed to: a) evaluate hamster as a model for insulin resistance, hyperlipidemia and atherosclerosis; and b) investigate the effect of a PPAR-α activator, fenofibrate, in this model. A high fat high cholesterol (HFHC) diet increased serum cholesterol and triglycerides, but inclusion of fenofibrate in the diet decreased cholesterol and proatherogenic lipoproteins, VLDL and LDL, in a time-dependent manner. Concomitantly, serum levels of triglycerides also decreased. These reductions were attributed, in part, to the down-regulation of lipogenic genes and upregulation of lipoprotein lipase. The HFHC diet caused body weight gain and mild insulin resistance, both of which were prevented following the treatments with fenofibrate. Insulin resistance was further investigated in high fructose-fed hamsters. Fenofibrate prevented both hyperinsulinemia and hypertriglyceridemia. The insulin sensitizing activity of fenofibrate appeared to occur via reductions in protein tyrosine phophatase-1B. To determine whether lowering of lipids by fenofibrate treatment contributed to the reduced risks of developing atherosclerosis in hyperlipidemic hamsters, we measured lipid deposition in the aorta. Our results showed that fenofibrate treatment reduced aortic lipid deposition by 70%. These findings suggest that hamster may be an adequate animal model to evaluate the efficacy of lipid lowering, insulin sensitizing and antiatherosclerotic agents. We also show that fenofibrate is an effective antiatherosclerotic agent in hyperlipidemic hamster model.

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References

  1. Shepherd J, Caslake MJ, Lorimer AR, Vallance BD, Packard CJ (1985) Fenofibrate reduces low density lipoprotein catabolism in hypertriglyceridemic subjects. Arteriosclerosis 5:162–168

    CAS  PubMed  Google Scholar 

  2. Bilz S, Wagner S, Schmitz M, Bedynek A, Keller U, Demant T (2004) Effects of atorvastatin versus fenofibrate on apolipoprotein B-100 and apolipoprotein A-I kinetics in mixed hyperlipidemia. J Lipid Res 45:174–185

    Article  CAS  PubMed  Google Scholar 

  3. Srivastava RAK, Jahagirdar R, Azhar S, Sharma S, Bisgaier CL (2006) 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

    Article  CAS  PubMed  Google Scholar 

  4. Li AC, Binder CJ, Gutierrez A, Brown KK, Plotkin CR, Pattison JW, Valledor AF, Davis RA, Willson TM, Witztum JL, Palinski J, Glass CK (2004) Differential inhibition of macrophage foam-cell formation and atherosclerosis in mice by PPARα, β/δ, and γ. J Clin Investig 114:1564–1576

    CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  6. van der Hoogt CC, de Haan W, Westerterp M, Hoekstra M, Dallinga-Thie GM, Romijn JA, Princen HMG, Jukema JW, Havekes LM, Rensen PCN (2007) Fenofibrate increases HDL-cholesterol by reducing cholesteryl ester transfer protein expression. J Lipid Res 48:1763–1771

    Article  PubMed  Google Scholar 

  7. Guérin M, Bruckert E, Dolphin PJ, Turpin G, Chapman MJ (1996) Fenofibrate reduces plasma cholesteryl ester transfer from HDL to VLDL and normalizes the atherogenic, dense LDL profile in combined hyperlipidemia. Arterioscler Thromb Vasc Biol 11:763–772

    Google Scholar 

  8. Srivastava RAK, Jiao S, Tang J, Pfleger B, Kitchens RT, Schonfeld G (1991) In vivo regulation of low density lipoprotein receptor and apolipoprotein B gene expressions in inbred strains of mice by dietary fatty acids and cholesterol. Biochim Biophys Acta 1086:29–43

    CAS  PubMed  Google Scholar 

  9. Spady DK, Dietschy JM (1988) Sterol synthesis in vivo in 18 tissues of the squirrel monkey, guinea pig, rabbit, hamster, and rat. J Lipid Res 24:303–315

    Google Scholar 

  10. Dorfman SE, Smith DE, Osgood DP, Lichtenstein AH (2003) Study on diet-induced changes in lipoprotein metabolism in two strains of Golden-Syrian hamsters. J Nutr 133:4183–4188

    CAS  PubMed  Google Scholar 

  11. Carpentier A, Taghibiglou C, Leung N, Szeto L, Van Iderstine SC, Uffelman KD, Buckingham R, Adeli K, Lewis GF (2002) Ameliorated hepatic insulin resistance is associated with normalization of microsomal triglyceride transfer protein expression and reduction in very low density lipoprotein assembly and secretion in fructose-fed hamster. J Biol Chem 277:28795–28802

    Article  CAS  PubMed  Google Scholar 

  12. Nistor A, Bulla A, Filip DA, Radu A (1987) The hyperlipidemic hamster as a model of experimental atherosclerosis. Atherosclerosis 68:159–173

    Article  CAS  PubMed  Google Scholar 

  13. Guo Q, Wang PR, Milot DP, Ippolito MC, Hernandez M, Burton CA, Wright SD, Chao Y (2001) Regulation of lipid metabolism and gene expression by fenofibrate in hamsters. Biochim Biophys Acta 1533:220–232

    CAS  PubMed  Google Scholar 

  14. Wang PR, Guo Q, Ippolito M, Wu M, Milot D, Ventre J, Doebber T, Wright SD, Chao Y (2001) High fat fed hamster, a unique animal model for treatment of diabetic dyslipidemia with peroxisome proliferator activated receptor alpha selective agonists. Eur J Pharmacol 21(427):285–293

    Article  Google Scholar 

  15. Ohtani H, Hayashi K, Hirata Y, Dojo S, Nakashima K, Nishio E, Kurushima H, Saeki M, Kajiyama G (1990) Effects of dietary cholesterol and fatty acids on plasma cholesterol level and hepatic lipoprotein metabolism. J Lipid Res 31:1413–1422

    CAS  PubMed  Google Scholar 

  16. Liu G, Fan L, Redinger R (1991) The association of hepatic apoprotein and lipid metabolism in hamsters and rats. Comp Biochem Physiol 99A:223–228

    Article  CAS  Google Scholar 

  17. Taghibiglou C, Rudy D, Van Iderstine SC, Aiton A, Cavallo D, Cheung R, Adeli K (2000) Intracellular mechanism regulating apoB-containing lipoprotein assembly and secretion in primary hamster hepatocytes. J Lipid Res 41:499–513

    CAS  PubMed  Google Scholar 

  18. Quig D, Arbeeney C, Zilversmit D (1991) Effects of hyperlipidemias in hamsters on lipid transfer protein activity and unidirectional cholesteryl ester transfer in plasma. Biochim Biophys Acta 1083:257–264

    CAS  PubMed  Google Scholar 

  19. Srivastava RAK (1995) Increased apolipoprotein B100 mRNA by estrogen in inbred strains of mice occurs by decreased mRNA for RNA editing protein mRNA. Biochem Biophys Res Commun 212:381–387

    Article  CAS  PubMed  Google Scholar 

  20. Spady DK, Dietschy JM (1988) Interaction of dietary cholesterol and triglycerides in the regulation of hepatic very low density lipoprotein transport in the hamster. J Clin Investig 81:300–309

    Article  CAS  PubMed  Google Scholar 

  21. Taghibiglou C, Rashid-Kolvear F, Van Iderstine SC, Le-Tien H, Fantus IG, Lewis GF, Adeli K (2002) Hepatic very low density lipoprotein-ApoB overproduction is associated with attenuated hepatic insulin signaling and overexpression of protein-tyrosine phosphatase 1B in a fructose-fed hamster model of insulin resistance. J Biol Chem 277:793–803

    Article  CAS  PubMed  Google Scholar 

  22. Sheng Z, Otani H, Brown MS, Goldstein JL (1995) Independent regulation of sterol regulatory element-binding proteins 1 and 2 in hamster liver. Proc Natl Acad Sci USA 92:935–938

    Article  CAS  PubMed  Google Scholar 

  23. Berthou L, Duverger N, Emmanuel F, Langouet S, Auwerx J, Guillouzo A, Fruchart JC, Rubin E, Denefle P, Staels B, Branellec D (1996) Opposite regulation of human versus mouse apolipoprotein A-I by fibrates in human apolipoprotein A-I transgenic mice. J Clin Investig 97:2408–2416

    Article  CAS  PubMed  Google Scholar 

  24. Mukherjee R, Locke KT, Miao B, Meyers D, Monshizadegan H, Zhang R, Search D, Grimm D, Flynn M, Kevin M, O’Malley KM, Zhang L, Li J, Shi Y, Kennedy LJ, Blanar M, Cheng PT, Tino J, Srivastava RAK (2008) Novel PPARα agonists lower LDL and triglycerides, raise HDL and synergistically increase cholesterol excretion with an LXR agonist. J Pharmacol Exp Ther 327:716–726

    Article  CAS  PubMed  Google Scholar 

  25. Chinetti G, Lestavel S, Bocher V, Remaley AT, Neve B, Torra IP, Teissier E, Minnich A, Jaye M, Duverger N, Brewer HB, Fruchart JC, Clavey V, Staels B (2001) PPAR-alpha and PPAR-gamma activators induce cholesterol removal from human macrophage foam cells through stimulation of the ABCA1 pathway. Nat Med 7(1):53–58

    Article  CAS  PubMed  Google Scholar 

  26. Srivastava RAK (2002) Estrogen-induced regulation of the ABCA1 in mice: a possible mechanism of atheroprotection by estrogen. Mol Cell Biochem 240:67–73

    Article  CAS  PubMed  Google Scholar 

  27. Srivastava RAK, Srivastava N (2000) High-density lipoprotein, apolipoprotein A-I, and coronary artery disease. Review. Mol Cell Biochem 209:131–144

    Article  CAS  PubMed  Google Scholar 

  28. John M, Galla JM, Tuzcu EM, Wolski K, Kalidindi S, Nissen SE, Nicholls SJ (2007) Atherogenic dyslipidemia predicts accelerated progression of atherosclerosis in patients with coronary artery disease. Circulation 116:II_285–II_286 (Abstract)

    Google Scholar 

  29. Declercq V, Yeganeh B, Moshtaghi-Kashanian GR, Khademi H, Bahadori B, Moghadasian MH (2005) Paradoxical effects of fenofibrate and nicotinic acid in apoE-deficient mice. J Cardiovasc Pharmacol 46:18–24

    Article  CAS  PubMed  Google Scholar 

  30. Yeganeh B, Moshtaghi-Kashanian GR, Declercq V, Moghadasian MH (2005) Combination of dietary phytosterols plus niacin or fenofibrate: effects on lipid profile and atherosclerosis in apoE-KO mice. J Nutr Biochem 16:222–228

    Article  CAS  PubMed  Google Scholar 

  31. Srivastava RAK (2009) Fenofibrate ameliorates diabetic and dyslipidemic profiles in KKAy mice partly via down-regulation of 11β-HSD1, PEPCK and DGAT2. Comparison of PPARα, PPARγ, and liver x receptor agonists. Eur J Pharmacol 607:258–263

    Article  CAS  PubMed  Google Scholar 

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Acknowledgments

The authors would like to thank Khosrow Adeli, University of Toronto, Canada, for helping with the measurements of PTP1B and insulin receptor protein mass, to Michael E Pape for useful discussions, to Charles L Bisgaier for critical reading of the manuscript as well as many thoughtful discussions during the course of this study, and to the vivarium staff for helping with this study.

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  1. Shirley He

    Present address: University of Michigan, Ann Arbor, MI, USA

Authors and Affiliations

  1. Department of Pharmacology, Esperion Therapeutics Inc., Plymouth, MI, 48170, USA

    Rai Ajit K. Srivastava & Shirley He

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  1. Rai Ajit K. Srivastava
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Correspondence to Rai Ajit K. Srivastava.

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Srivastava, R.A.K., He, S. Anti-hyperlipidemic and insulin sensitizing activities of fenofibrate reduces aortic lipid deposition in hyperlipidemic Golden Syrian hamster. Mol Cell Biochem 345, 197–206 (2010). https://doi.org/10.1007/s11010-010-0573-8

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  • DOI: https://doi.org/10.1007/s11010-010-0573-8

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