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Overexpression of apolipoprotein CIII increases and CETP reverses diet-induced obesity in transgenic mice

International Journal of Obesity volume 31, pages 1586–1595 (2007)Cite this article

Abstract

Objective:

We recently described that hypertriglyceridemic apolipoprotein (apo) CIII transgenic mice show increased whole body metabolic rate. In this study, we used these apo CIII-expressing mice, combined or not with the expression of the natural promoter-driven CETP gene, to test the hypothesis that both proteins modulate diet-induced obesity.

Measurements and results:

Mice expressing apo CIII, CIII/CETP, CETP and nontransgenic (NonTg) mice were maintained on a high-fat diet (14% fat by weight) during 20 weeks after weaning. At the end of this period, all groups exhibited the expected lipemic phenotype. Fasting glucose levels were neither affected by the high-fat diet nor by the distinct genotypes. However, apo CIII mice showed significantly higher glycemia (∼35%) and lower insulin levels (∼45%) in the fed state, compared with the NonTg mice. The apo CIII mice presented significantly increased body weight, lipid content of the carcass (∼25%), visceral adipose tissue mass (about twofold) and adipocyte size (∼25%) compared with the CETP and NonTg mice. The CETP expression in the apo CIII background normalized the subcutaneous adipose depot and visceral adipocyte size to the levels of NonTg mice. Plasma leptin levels were lower in CETP groups (25–50%) and higher in the apo CIII mice. Similar core body temperature in all groups and similar liver mitochondrial resting respiration rates in CIII and NonTg mice indicate no differences in basal energy expenditure rates among these mice fed a high-fat diet.

Conclusion:

The elevation of plasma apo CIII levels aggravates diet-induced obesity and the expression of physiological levels of circulating CETP reverses this adipogenic effect, indicating a novel role for CETP in modulating adiposity.

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References

  1. Mancini M, Steiner G, Betteridge DJ, Pometta D . Acquired (secondary) forms of hypertriglyceridemia. Am J Cardiol 1991; 68: A17–A21.

    Article  Google Scholar 

  2. Assmann G, Brewer Jr HB . Genetic (primary) forms of hypertriglyceridemia. Am J Cardiol 1991; 68: A13–A16.

    Article  Google Scholar 

  3. Jong MC, Hofker MH, Havekes LM . Role of apoCs in lipoprotein metabolism: functional differences between apoC1, apoC2, and apoC3. Arterioscle Thromb Vas Biol 1999; 19: 472–484.

    Article  CAS  Google Scholar 

  4. Jong MC, Rensen PC, Dahlmans VE, Van Der Boom H, Van Berkel TJ, Havekes LM . Apolipoprotein C-III deficiency accelerates triglyceride hydrolysis by lipoprotein lipase in wild-type and apoE knockout mice. J Lipid Res 2001; 42: 1578–1585.

    CAS  PubMed  Google Scholar 

  5. Kashyap ML, Srivasta LS, Hynd BA, Gartside PS, Perisutti G . Quantitation of human apolipoprotein C-III and its subspecies by radioimmunoassay and analytical isoelectric focusing: abnormal plasma triglyceride-rich lipoprotein apolipoprotein C-III subspecie concentrations in hypertriglyceridemia. J Lipid Res 1981; 22: 800–810.

    CAS  PubMed  Google Scholar 

  6. Fredenrich A, Giroux LM, Tremblay M, Krimbou L, Davignon J, Cohn JS . Plasma lipoprotein distribution of apoC-III in normolipidemic and hypertriglyceridemic subjects: comparison of the apoCIII to apoE ratio in different lipoprotein fractions. J Lipid Res 1997; 38: 1421–1432.

    CAS  PubMed  Google Scholar 

  7. Ito Y, Azrolan N, O’connell A, Walsh A, Breslow JL . Hypertriglyceridemia as a result of human apolipoprotein C-III gene expression in transgenic mice. Science 1990; 249: 790–793.

    Article  CAS  Google Scholar 

  8. Aalto-Setala K, Fisher EA, Chen X, Chajekshaul T, Hayek T, Zechner R et al. Mechanism of hypertriglyceridemia in human apolipoprotein (apo) C-III transgenic mice: diminished very low density lipoprotein fractional catabolic rate associated with increased apoCIII and reduced apoE on the particles. J Clin Invest 1992; 90: 1889–1900.

    Article  CAS  Google Scholar 

  9. De Silva HV, Lauer SJ, Wang J, Simonett WS, Weisgraber KH, Mahley RW et al. Overexpression of human apolipoprotein C-III in transgenic mice results in accumulation of apolipoprotein B48 remnant that is corrected by excess apolipoprotein E. J Biol Chem 1994; 269: 2324–2335.

    CAS  PubMed  Google Scholar 

  10. Forte TM, Nichols AV, Krauss RM, Norum RA . Familial apolipoprotein AI and apolipoprotein CIII deficiency. Subclass distribution, composition, and morphology of lipoproteins in a disorder associated with premature atherosclerosis. J Clin Invest 1984; 74: 1601–1613.

    Article  CAS  Google Scholar 

  11. Von Eckardstein A, Holz H, Sandkamp M, Weng W, Funke H, Assmann G . Apolipoprotein C-III(Lys58- - - -Glu). Identification of an apolipoprotein C-III variant in a family with hyperalphalipoproteinemia. J Clin Invest 1991; 87: 1724–1731.

    Article  CAS  Google Scholar 

  12. Maeda N, Li H, Lee D, Oliver P, Quarfordt SH, Osada J . Targeted disruption of the apolipoprotein C-III gene in mice results in hypotriglyceridemia and protection from postprandial hypertriglyceridemia. J Biol Chem 1994; 269: 10–16.

    Google Scholar 

  13. Ebara T, Ramakrishnan R, Steiner G, Shachter NS . Chylomicronemia due to apolipoprotein C-III overexpression in apolipoprotein E-null mice: apolipoprotein C-III-induced hypertriglyceridemia is not mediated by effects on apoE. J Clin Invest 1997; 99: 2672–2681.

    Article  CAS  Google Scholar 

  14. Kowal RC, Herz J, Weisgraber KH, Mahley RW, Brown MS, Goldstein JL . Opposing effects of apolipoprotein E and C on lipoprotein binding to low density lipoprotein receptor-related protein. J Biol Chem 1990; 265: 10771–10779.

    CAS  PubMed  Google Scholar 

  15. Sehayek E, Eisenberg S . Mechanisms of inhibition by apolipoprotein C of apolipoprotein E-dependent cellular metabolism of human triglyceride-rich lipoproteins through the low-density lipoprotein receptor pathway. J Biol Chem 1991; 266: 18259–18267.

    CAS  PubMed  Google Scholar 

  16. Aalto-Setala K, Weinstock PH, Bisgaier CL, Wu L, Smith JD, Breslow JL . Further characterization of the metabolic properties of triglyceride-rich lipoproteins from human and mouse apoC-III transgenic mice. J Lipid Res 1996; 37: 1802–1811.

    CAS  PubMed  Google Scholar 

  17. Tall AR . Plasma cholesteryl ester transfer protein. J Lipid Res 1993; 34: 1255–1274.

    CAS  PubMed  Google Scholar 

  18. Ha YC, Barter PJ . Differences in plasma cholesteryl ester transfer activity in sixteen vertebrate species. Comp Biochem Physiol B 1982; 71: 265–269.

    Article  CAS  Google Scholar 

  19. Jiang X, Moulin P, Quinet E, Goldberg IJ, Yacoub LK, Agellon LB et al. Mammalian adipose tissue and muscle are major sources of lipid transfer protein mRNA. J Biol Chem 1991; 266: 4631–4639.

    CAS  PubMed  Google Scholar 

  20. Agellon LB, Walsh A, Hayek T, Moulin P, Jiang XC, Shelanski SA et al. Reduced high density lipoprotein cholesterol in human cholesteryl ester transfer protein transgenic mice. J Biol Chem 1991; 266: 10796–10801.

    CAS  PubMed  Google Scholar 

  21. Jiang XC, Agellon LB, Walsh A, Breslow JL, Tall AR . Dietary cholesterol increases transcription of the human cholesteryl ester transfer protein gene in transgenic mice. Dependence on natural flanking sequences. J Clin Invest 1992; 90: 1290–1295.

    Article  CAS  Google Scholar 

  22. Marotti KR, Castle CK, Boyle TP, Lin AH, Murray RW, Melchior GW . Severe atherosclerosis in transgenic mice expressing simian cholesteryl ester transfer protein. Nature 1993; 364: 73–75.

    Article  CAS  Google Scholar 

  23. Plump AS, Masucci-Magoulas L, Bruce C, Bisgaier CL, Breslow JL, Tall AR . Increased atherosclerosis in ApoE and LDL receptor gene knock-out mice as a result of human cholesteryl ester transfer protein transgene expression. Arterioscler Thromb Vasc Biol 1999; 19: 1105–1110.

    Article  CAS  Google Scholar 

  24. Harada LM, Amigo L, Cazita PM, Salerno AG, Rigotti AA, Quintão EC et al. CETP expression enhances liver HDL-cholesteryl ester uptake but does not alter VLDL and biliary lipid secretion. Atherosclerosis 2007; 191: 313–318.

    Article  CAS  Google Scholar 

  25. Vassiliou G, Mcpherson R . Role of cholesteryl ester transfer protein in selective uptake of high-density lipoprotein cholesteryl esters by adipocytes. J Lipid Res 2004; 45: 1683–1693.

    Article  CAS  Google Scholar 

  26. Gauthier A, Lau P, Zha X, Milne R, Mcpherson R . Cholesteryl ester transfer protein directly mediates selective uptake of high-density lipoprotein cholesteryl esters by the liver. Arterioscler Thromb Vasc Biol 2005; 25: 2177–2184.

    Article  CAS  Google Scholar 

  27. Hayek T, Masucci-Magoulas L, Jiang X, Walsh A, Rubin E, Breslow JL et al. Decreased early atherosclerotic lesions in hypertriglyceridemic mice expressing cholesteryl ester transfer protein transgene. J Clin Invest 1995; 96: 2071–2074.

    Article  CAS  Google Scholar 

  28. Cazita PM, Berti JA, Aoki C, Gidlund M, Harada LM, Nunes VS et al. Cholesteryl ester transfer protein expression attenuates atherosclerosis in ovariectomized mice. J Lipid Res 2003; 44: 33–40.

    Article  CAS  Google Scholar 

  29. Casquero AC, Berti JA, Salerno AG, Bighetti EJ, Cazita PM, Ketelhth DF et al. Atherosclerosis is enhanced by testosterone deficiency and attenuated by CETP expression in transgenic mice. J Lipid Res 2006; 47: 1526–1534.

    Article  CAS  Google Scholar 

  30. Clark RW . Raising high-density lipoprotein with cholesteryl ester transfer protein inhibitors. Curr Opin Pharmacol 2006; 6: 162–168.

    Article  CAS  Google Scholar 

  31. Pearson H . When good cholesterol turns bad. Nature 2006; 444: 794–795.

    Article  CAS  Google Scholar 

  32. Tall AR, Yvan-Charvet L, Wang N . The failure of torcetrapib: was it the molecule or the mechanism? Arterioscler Thromb Vasc Biol 2007; 27: 257–260.

    Article  CAS  Google Scholar 

  33. Zhou H, Li Z, Hojjati MR, Jang D, Beyer TP, Cao G et al. Adipose tissue specific CETP expression in mice: impact on lipoprotein metabolism. J Lipid Res 2006; 47: 2011–2019.

    Article  CAS  Google Scholar 

  34. Alberici LC, Oliveira HCF, Patrício PR, Kowaltowski AJ, Vercesi AE . Hyperlipidemic mice present enhanced catabolism and higher mitochondrial ATP-sensitive K+ channel activity. Gastroenterology 2006; 131: 1228–1234.

    Article  CAS  Google Scholar 

  35. Duivenvoorden I, Teusink B, Rensen PC, Romijn JA, Havekes LM, Voshol PJ . Apolipoprotein C3 deficiency results in diet-induced obesity and aggravated insulin resistance in mice. Diabetes 2005; 54: 664–671.

    Article  CAS  Google Scholar 

  36. Jong MC, Voshol PJ, Muurling M, Dahlmans VE, Romijn JA, Pijl H et al. Protection from obesity and insulin resistance in mice overexpressing human apolipoprotein C1. Diabetes 2001; 50: 2779–2785.

    Article  CAS  Google Scholar 

  37. Walsh A, Azrolan N, Wang K, Marcigliano A, O’connell A, Breslow JL . Intestinal expression of the human apoA-I gene in transgenic mice is controlled by a DNA region 3’ to the gene in the promoter of the adjacent convergently transcribed apoC-III gene. J Lipid Res 1993; 34: 617–623.

    CAS  PubMed  Google Scholar 

  38. Berti JA, Amaral ME, Boschero AC, Nunes VS, Harada LM, Castilho LN et al. Thyroid hormone increases plasma cholesteryl ester transfer protein activity and plasma high-density lipoprotein removal rate in transgenic mice. Metabolism 2001; 50: 530–536.

    Article  CAS  Google Scholar 

  39. Scott AM, Atwater I, Rojas E . A method for the simultaneous measurement of insulin release and B cell membrane potential in single mouse islets of Langerhans. Diabetologia 1981; 21: 470–475.

    Article  CAS  Google Scholar 

  40. Rodbell M . Metabolism of isolated fat cells. Effects of hormones on glucose metabolism and lipolysis. J Biol Chem 1964; 239: 375–380.

    CAS  PubMed  Google Scholar 

  41. Kaplan RS, Pedersen PL . Characterization of phosphate efflux pathways in rat liver mitochondria. Biochem J 1983; 212: 279–288.

    Article  CAS  Google Scholar 

  42. Boschero AC, Szpak-Glasman M, Carneiro EM, Bordin S, Paul I, Rojas E et al. Oxotremorine-m potentiation of glucose-induced insulin release from rat islets involves M3 muscarinic receptors. Am J Physiol 1995; 268: E336–E342.

    CAS  PubMed  Google Scholar 

  43. Van Harmelen V, Dicker A, Rydén M, Hauner H, Lonnqvist F, Naslund E et al. Increased lipolysis and decreased leptin production by human omental as compared with subcutaneos preadipocytes. Diabetes 2002; 51: 2029–2036.

    Article  CAS  Google Scholar 

  44. Amaral ME, Oliveira HCF, Carneiro EM, Delghingaro-Augusto V, Vieira EC, Berti JA et al. Plasma glucose regulation and insulin secretion in hypertriglyceridemic mice. Horm Metab Res 2002; 34: 21–26.

    Article  CAS  Google Scholar 

  45. Reaven GM, Mondon CE, Chen YD, Breslow JL . Hypertriglyceridemic mice transgenic for the human apolipoprotein C-III gene are neither insulin resistant nor hyperinsulinemic. J Lipid Res 1994; 35: 820–824.

    CAS  PubMed  Google Scholar 

  46. Biddinger SB, Kahn CR . From mice to men: insights into the insulin resistance syndromes. Annu Rev Physiol 2006; 68: 123–158.

    Article  CAS  Google Scholar 

  47. Yin W, Liao D, Kusunoki M, Xi S, Tsutsumi K, Wang Z et al. NO-1886 decreases ectopic lipid deposition and protects pancreatic beta cells in diet-induced diabetic swine. J Endocrinol 2004; 180: 399–408.

    Article  CAS  Google Scholar 

  48. Araujo EP, De Souza CT, Gasparetti AL, Ueno M, Boschero AC, Saad MJ et al. Short-term in vivo inhibition of insulin receptor substrate-1 expression leads to insulin resistance, hyperinsulinemia, and increased adiposity. Endocrinology 2005; 146: 1428–1437.

    Article  CAS  Google Scholar 

  49. Conde-Knape K, Okada K, Ramakrishnan R, Shachter NS . Overexpression of apoC-III produces lesser hypertriglyceridemia in apoB-48-only gene-targeted mice than in apoB-100-only mice. J Lipid Res 2004; 45: 2235–2244.

    Article  CAS  Google Scholar 

  50. Le Lay S, Krief S, Farnier C, Lefrere I, Le Liepvre X, Bazin R et al. Cholesterol, a cell size-dependent signal that regulates glucose metabolism and gene expression in adipocytes. J Biol Chem 2001; 276: 16904–16910.

    Article  CAS  Google Scholar 

  51. Asayama K, Hayashibe H, Dobashi K, Uchida N, Nakane T, Kodera K et al. Increased serum cholesteryl ester transfer protein in obese children. Obes Res 2002; 10: 439–446.

    Article  CAS  Google Scholar 

  52. Arai T, Yamashita S, Hirano K, Sakai N, Kotani K, Fujioka S et al. Increased plasma cholesteryl ester transfer protein in obese subjects. A possible mechanism for the reduction of serum HDL cholesterol levels in obesity. Arterioscler Thromb 1994; 14: 1129–1136.

    Article  CAS  Google Scholar 

  53. Teran-Garcia M, Despres JP, Tremblay A, Bouchard C . Effects of cholesterol ester transfer protein (CETP) gene on adiposity in response to long-term overfeeding. Atherosclerosis 2006 [ahead of print, DOI: 10.1016/j.atherosclerosis.2006.12.005].

    Article  Google Scholar 

  54. Boekholdt SM, Thompson JF . Natural genetic variation as a tool in understanding the role of CETP in lipid levels and disease. J Lipid Res 2003; 44: 1080–1093.

    Article  CAS  Google Scholar 

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Acknowledgements

This study is part of the PhD thesis of AG Salerno and was supported by grants from Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP) and Conselho Nacional para o Desenvolvimento Científico e Tecnológico (CNPq). We are grateful to Lécio D Teixeira for animal caring.

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Authors and Affiliations

  1. Departamento de Fisiologia e Biofísica, Instituto de Biologia, Universidade Estadual de Campinas, Campinas, SP, Brazil

    A G Salerno, T R Silva, M E C Amaral, M L Bonfleur, P R Patrício, E P M S Francesconi, D M Grassi-Kassisse, A C Boschero & H C F Oliveira

  2. Departamento Patologia Clínica, Faculdade de Ciências Médicas, Universidade Estadual de Campinas, Campinas, SP, Brazil

    L C Alberici & A E Vercesi

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  1. A G Salerno
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  2. T R Silva
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Correspondence to H C F Oliveira.

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Salerno, A., Silva, T., Amaral, M. et al. Overexpression of apolipoprotein CIII increases and CETP reverses diet-induced obesity in transgenic mice. Int J Obes 31, 1586–1595 (2007). https://doi.org/10.1038/sj.ijo.0803646

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