Acta Diabetologica

, Volume 51, Issue 1, pp 23–30 | Cite as

Low density lipoprotein receptor–related protein 1 is upregulated in epicardial fat from type 2 diabetes mellitus patients and correlates with glucose and triglyceride plasma levels

  • L. Nasarre
  • O. Juan-Babot
  • P. Gastelurrutia
  • A. Llucia-Valldeperas
  • L. Badimon
  • A. Bayes-Genis
  • V. Llorente-Cortés
Original Article

Abstract

Lipoprotein receptor expression plays a crucial role in the pathophysiology of adipose tissue in in vivo models of diabetes. However, there are no studies in diabetic patients. The aims of this study were to analyze (a) low-density lipoprotein receptor–related protein 1 (LRP1) and very low-density lipoprotein receptor (VLDLR) expression in epicardial and subcutaneous fat from type 2 diabetes mellitus compared with nondiabetic patients and (b) the possible correlation between the expression of these receptors and plasmatic parameters. Adipose tissue biopsy samples were obtained from diabetic (n = 54) and nondiabetic patients (n = 22) undergoing cardiac surgery before the initiation of cardiopulmonary bypass. Adipose LRP1 and VLDLR expression was analyzed at mRNA level by real-time PCR and at protein level by Western blot analysis. Adipose samples were also subjected to lipid extraction, and fat cholesterol ester, triglyceride, and free cholesterol contents were analyzed by thin-layer chromatography. LRP1 expression was higher in epicardial fat from diabetic compared with nondiabetic patients (mRNA 17.63 ± 11.37 versus 7.01 ± 4.86; P = 0.02; protein 11.23 ± 7.23 versus 6.75 ± 5.02, P = 0.04). VLDLR expression was also higher in epicardial fat from diabetic patients but only at mRNA level (231.25 ± 207.57 versus 56.64 ± 45.64, P = 0.02). No differences were found in the expression of LRP1 or VLDLR in the subcutaneous fat from diabetic compared with nondiabetic patients. Epicardial LRP1 and VLDLR mRNA overexpression positively correlated with plasma triglyceride levels (R2 = 0.50, P = 0.01 and R2 = 0.44, P = 0.03, respectively) and epicardial LRP1 also correlated with plasma glucose levels (R2 = 0.33, P = 0.03). These results suggest that epicardial overexpression of certain lipoprotein receptors such as LRP1 and VLDLR expression may play a key role in the alterations of lipid metabolism associated with type 2 diabetes mellitus.

Keywords

Epicardial fat LRP1 VLDLR Type 2 diabetes Triglycerides 

Notes

Acknowledgments

This work was funded by grants from Instituto de Salud Carlos III, REDINSCOR RD06/0003/0015 (V. Llorente-Cortés and O. Juan-Babot), FIS PI11/00747 cofinanced by Fondo Europeo de Desarrollo Regional (F.E.D.E.R) and by Fundació MARATÓ TV3 (080110). The authors thank Dr. Vicenç Martí (Interventional Cardiology Unit, Hospital de la Santa Creu i Sant Pau-UAB, Barcelona) by his help with data collection and statistics.

Conflict of interest

The authors declare that they have no conflicts of interest

References

  1. 1.
    Sironi AM, Gastaldelli A, Mari A, Ciociaro D, Positano V, Buzzigoli E, Ghione S, Turchi S, Lombardi M, Ferrannini E (2004) Visceral fat in hypertension: influence on insulin resistance and beta-cell function. Hypertension 44:127–133PubMedCrossRefGoogle Scholar
  2. 2.
    Kankaanpää M, Lehto HR, Pärkkä JP, Komu M, Viljanen A, Ferrannini E, Knuuti J, Nuutila P, Parkkola R, Iozzo P (2006) Myocardial triglyceride content and epicardial fat mass in human obesity: relationship to left ventricular function and serum free fatty acid levels. J Clin Endocrinol Metab 91:4689–4695PubMedCrossRefGoogle Scholar
  3. 3.
    Mahabadi AA, Massaro JM, Rosito GA, Levy D, Murabito JM, Wolf PA, O’Donnell CJ, Fox CS, Hoffmann U (2009) Association of pericardial fat, intrathoracic fat, and visceral abdominal fat with cardiovascular disease burden: the Framingham Heart Study. Eur Heart J 30:850–856PubMedCrossRefGoogle Scholar
  4. 4.
    Iacobellis G, Ribaudo MC, Assael F, Vecci E, Tiberti C, Zappaterreno A, Di Mario U, Leonetti F (2003) Echocardiographic epicardial adipose tissue is related to anthropometric and clinical parameters of metabolic syndrome: a new indicator of cardiovascular risk. J Clin Endocrinol Metab 88:5163–5168PubMedCrossRefGoogle Scholar
  5. 5.
    Mazurek T, Zhang L, Zalewski A, Mannion JD, Diehl JT, Arafat H, Sarov-Blat L, O’Brien S, Keiper EA, Johnson AG, Martin J, Goldstein BJ, Shi Y (2003) Human epicardial adipose tissue is a source of inflammatory mediators. Circulation 108:2460–2466PubMedCrossRefGoogle Scholar
  6. 6.
    Baker AR, Silva NF, Quinn DW, Harte AL, Pagano D, Bonser RS, Kumar S, McTernan PG (2006) Human epicardial adipose tissue expresses a pathogenic profile of adipocytokines in patients with cardiovascular disease. Cardiovasc Diabetol 13(5):1CrossRefGoogle Scholar
  7. 7.
    Djaberi R, Schuijf JD, van Werkhoven JM, Nucifora G, Jukema JW, Bax JJ (2008) Relation of epicardial adipose tissue to coronary atherosclerosis. Am J Cardiol 102:1602–1607PubMedCrossRefGoogle Scholar
  8. 8.
    Taguchi R, Takasu J, Itani Y, Yamamoto R, Yokoyama K, Watanabe S, Masuda Y (2001) Pericardial fat accumulation in men as a risk factor for coronary artery disease. Atherosclerosis 157:203–209PubMedCrossRefGoogle Scholar
  9. 9.
    Salgado-Somoza A, Teijeira-Fernández E, Fernández AL, González-Juanatey JR, Eiras S (2010) Proteomic analysis of epicardial and subcutaneous adipose tissue reveals differences in proteins involved in oxidative stress. Am J Physiol Heart Circ Physiol 299:H202–H209PubMedCrossRefGoogle Scholar
  10. 10.
    Rijzewijk LJ, van der Meer RW, Smit JW, Diamant M, Bax JJ, Hammer S, Romijn JA, de Roos A, Lamb HJ (2008) Myocardial steatosis is an independent predictor of diastolic dysfunction in type 2 diabetes mellitus. J Am Coll Cardiol 52:1793–1799PubMedCrossRefGoogle Scholar
  11. 11.
    Castellano J, Farré J, Fernandes J, Bayes-Genis A, Cinca J, Badimon L, Hove-Madsen L, Llorente-Cortés V (2011) Hypoxia exacerbates Ca(2+)-handling disturbances induced by very low density lipoproteins (VLDL) in neonatal rat cardiomyocytes. J Mol Cell Cardiol 50:894–902PubMedCrossRefGoogle Scholar
  12. 12.
    Cal R, Castellano J, Revuelta-López E, Aledo R, Barriga M, Farré J, Vilahur G, Nasarre L, Hove-Madsen L, Badimon L, Llorente-Cortés V (2012) Low-density lipoprotein receptor-related protein 1 mediates hypoxia-induced very low density lipoprotein-cholesteryl ester uptake and accumulation in cardiomyocytes. Cardiovasc Res 94:469–479PubMedCrossRefGoogle Scholar
  13. 13.
    Yagyu H, Lutz EP, Kako Y, Marks S, Hu Y, Choi SY, Bensadoun A, Goldberg IJ (2002) Very low density lipoprotein (VLDL) receptor-deficient mice have reduced lipoprotein lipase activity. Possible causes of hypertriglyceridemia and reduced body mass with VLDL receptor deficiency. J Biol Chem 277:10037–10043PubMedCrossRefGoogle Scholar
  14. 14.
    Goudriaan JR, Tacken PJ, Dahlmans VE, Gijbels MJ, van Dijk KW, Havekes LM, Jong MC (2001) Protection from obesity in mice lacking the VLDL receptor. Arterioscler Thromb Vasc Biol 21:1488–1493PubMedCrossRefGoogle Scholar
  15. 15.
    Descamps O, Bilheimer D, Herz J (1993) Insulin stimulates receptor-mediated uptake of apoE-enriched lipoproteins and activated alpha 2-macroglobulin in adipocytes. J Biol Chem 268:974–981PubMedGoogle Scholar
  16. 16.
    Gauthier A, Vassiliou G, Benoist F, McPherson R (2003) Adipocyte low density lipoprotein receptor-related protein gene expression and function is regulated by peroxisome proliferator-activated receptor gamma. J Biol Chem 278:11945–11953PubMedCrossRefGoogle Scholar
  17. 17.
    Hofmann SM, Zhou L, Perez-Tilve D, Greer T, Grant E, Wancata L, Thomas A, Pfluger PT, Basford JE, Gilham D, Herz J, Tschöp MH, Hui DY (2007) Adipocyte LDL receptor-related protein-1 expression modulates postprandial lipid transport and glucose homeostasis in mice. J Clin Invest 117:3271–3282PubMedCentralPubMedCrossRefGoogle Scholar
  18. 18.
    Llorente-Cortés V, Otero-Viñas M, Sánchez S, Rodríguez C, Badimon L (2002) Low-density lipoprotein upregulates low-density lipoprotein receptor-related protein expression in vascular smooth muscle cells: possible involvement of sterol regulatory element binding protein-2-dependent mechanism. Circulation 106:3104–3110PubMedCrossRefGoogle Scholar
  19. 19.
    Llorente-Cortés V, Costales P, Bernués J, Camino-Lopez S, Badimon L (2006) Sterol regulatory element-binding protein-2 negatively regulates low density lipoprotein receptor-related protein transcription. J Mol Biol 359:950–960PubMedCrossRefGoogle Scholar
  20. 20.
    Costales P, Aledo R, Vérnia S, Das A, Shah VH, Casado M, Badimon L, Llorente-Cortés V (2010) Selective role of sterol regulatory element binding protein isoforms in aggregated LDL-induced vascular low density lipoprotein receptor-related protein-1 expression. Atherosclerosis 213:458–468PubMedCrossRefGoogle Scholar
  21. 21.
    Sendra J, Llorente-Cortés V, Costales P, Huesca-Gómez C, Badimon L (2008) Angiotensin II upregulates LDL receptor-related protein (LRP1) expression in the vascular wall: a new pro-atherogenic mechanism of hypertension. Cardiovasc Res 78:581–589PubMedCrossRefGoogle Scholar
  22. 22.
    Bayes-Genis A, Soler-Botija C, Farré J, Sepúlveda P, Raya A, Roura S, Prat-Vidal C, Gálvez-Montón C, Montero JA, Büscher D, Izpisúa Belmonte JC (2010) Human progenitor cells derived from cardiac adipose tissue ameliorate myocardial infarction in rodents. J Mol Cell Cardiol 49:771–780PubMedCrossRefGoogle Scholar
  23. 23.
    Bligh EG, Dyer WJ (1959) A rapid method of total lipid extraction and purification. Can J Biochem Physiol 37:911–917PubMedCrossRefGoogle Scholar
  24. 24.
    Rydén L, Standl E, Bartnik M, Van den Berghe G, Betteridge J, de Boer MJ, Cosentino F, Jönsson B, Laakso M, Malmberg K, Priori S, Ostergren J, Tuomilehto J, Thrainsdottir I, Vanhorebeek I, Stramba-Badiale M, Lindgren P, Qiao Q, Priori SG, Blanc JJ, Budaj A, Camm J, Dean V, Deckers J, Dickstein K, Lekakis J, McGregor K, Metra M, Morais J, Osterspey A, Tamargo J, Zamorano JL, Deckers JW, Bertrand M, Charbonnel B, Erdmann E, Ferrannini E, Flyvbjerg A, Gohlke H, Juanatey JR, Graham I, Monteiro PF, Parhofer K, Pyörälä K, Raz I, Schernthaner G, Volpe M, Wood D; Task Force on Diabetes and Cardiovascular Diseases of the European Society of Cardiology (ESC); European Association for the Study of Diabetes (EASD), Guidelines on diabetes, pre-diabetes, and cardiovascular diseases: executive summary (2007) The task force on diabetes and cardiovascular diseases of the European Society of Cardiology (ESC) and of the European Association for the Study of Diabetes (EASD). Eur Heart J 28:88–136Google Scholar
  25. 25.
    Gaborit B, Kober F, Jacquier A, Moro PJ, Cuisset T, Boullu S, Dadoun F, Alessi MC, Morange P, Clément K, Bernard M, Dutour A (2012) Assessment of epicardial fat volume and myocardial triglyceride content in severely obese subjects:relationship to metabolic profile, cardiac function and visceral fat. Int J Obes (Lond) 36:422–430CrossRefGoogle Scholar
  26. 26.
    Yerramasu A, Dey D, Venuraju S, Anand DV, Atwal S, Corder R, Berman DS, Lahiri A (2012) Increased volume of epicardial fat is an independent risk factor for accelerated progression of sub-clinical coronary atherosclerosis. Atherosclerosis 220:223–230PubMedCrossRefGoogle Scholar
  27. 27.
    Harmancey R, Wilson CR, Taegtmeyer H (2008) Adaptation and maladaptation of the heart in obesity. Hypertension 52:181–187PubMedCentralPubMedCrossRefGoogle Scholar
  28. 28.
    Sell H, Dietze-Schroeder D, Eckel J (2006) The adipocyte-myocyte axis in insulin resistance. Trends Endocrinol Metab 17:416–422PubMedCrossRefGoogle Scholar
  29. 29.
    Cal R, Juan-Babot O, Brossa V, Roura S, Galvez-Monton C, Portoles M, Rivera M, Cinca J, Badimon L, Llorente-Cortes V (2012) Low density lipoprotein receptor-related protein 1 expression correlatos with cholesteryl ester accumulation in the myocardium of ischemic cardiomyopathy patients. J Transl Med 10:160Google Scholar
  30. 30.
    Castellano J, Aledo R, Sendra J, Costales P, Juan-Babot O, Badimon L, Llorente-Cortés V (2011) Hypoxia stimulates low-density lipoprotein receptor-related protein-1 expression through hypoxia-inducible factor-1α in human vascular smooth muscle cells. Arterioscler Thromb Vasc Biol 31:1411–1420PubMedCrossRefGoogle Scholar
  31. 31.
    Masson O, Chavey C, Dray C, Meulle A, Daviaud D, Quilliot D, Muller C, Valet P, Liaudet-Coopman E (2009) LRP1 receptor controls adipogenesis and is up-regulated in human and mouse obese adipose tissue. PLoS ONE 4:e7422PubMedCentralPubMedCrossRefGoogle Scholar
  32. 32.
    Clemente-Postigo M, Queipo-Ortuño MI, Fernandez-Garcia D, Gomez-Huelgas R, Tinahones FJ, Cardona F (2011) Adipose tissue gene expression of factors related to lipid processing in obesity. PLoS ONE 6:e24783PubMedCentralPubMedCrossRefGoogle Scholar
  33. 33.
    Corvera S, Graver DF, Smith RM, Insulin increases the cell surface concentration of alpha 2-macroglobulin receptors in 3T3-L1 adipocytes (1989) Altered transit of the receptor among intracellular endocytic compartments. J Biol Chem 264:10133–10138PubMedGoogle Scholar
  34. 34.
    Jedrychowski MP, Gartner CA, Gygi SP, Zhou L, Herz J, Kandror KV, Pilch PF (2010) Proteomic analysis of GLUT4 storage vesicles reveals LRP1 to be an important vesicle component and target of insulin signaling. J Biol Chem 285:104–114PubMedCrossRefGoogle Scholar
  35. 35.
    Bogan JS (2012) Regulation of glucose transporter translocation in health and diabetes. Annu Rev Biochem 81:507–532PubMedCrossRefGoogle Scholar
  36. 36.
    Dicker A, Le Blanc K, Aström G, van Harmelen V, Götherström C, Blomqvist L, Arner P, Rydén M (2005) Functional studies of mesenchymal stem cells derived from adult human adipose tissue. Exp Cell Res 308:283–290PubMedCrossRefGoogle Scholar
  37. 37.
    Iwasaki T, Takahashi S, Takahashi M, Zenimaru Y, Kujiraoka T, Ishihara M, Nagano M, Suzuki J, Miyamori I, Naiki H, Sakai J, Fujino T, Miller NE, Yamamoto TT, Hattori H (2005) Deficiency of the very low-density lipoprotein (VLDL) receptors in streptozotocin-induced diabetic rats: insulin dependency of the VLDL receptor. Endocrinology 146:3286–3294PubMedCrossRefGoogle Scholar
  38. 38.
    Takazawa T, Yamauchi T, Tsuchida A, Takata M, Hada Y, Iwabu M, Okada-Iwabu M, Ueki K, Kadowaki T (2009) Peroxisome proliferator-activated receptor gamma agonist rosiglitazone increases expression of very low density lipoprotein receptor gene in adipocytes. J Biol Chem 284:30049–30057PubMedCrossRefGoogle Scholar
  39. 39.
    Takahashi S, Sakai J, Fujino T, Hattori H, Zenimaru Y, Suzuki J, Miyamori I, Yamamoto TT (2004) The very low-density lipoprotein (VLDL) receptor: characterization and functions as a peripheral lipoprotein receptor. J Atheroscler Thromb 11:200–208PubMedCrossRefGoogle Scholar
  40. 40.
    Prawitt J, Niemeier A, Kassem M, Beisiegel U, Heeren J (2008) Characterization of lipid metabolism in insulin-sensitive adipocytes differentiated from immortalized human mesenchymal stem cells. Exp Cell Res 314:814–824PubMedCrossRefGoogle Scholar
  41. 41.
    Kahn SE, Hull RL, Utzschneider KM (2006) Mechanisms linking obesity to insulin resistance and type 2 diabetes. Nature 444:840–846PubMedCrossRefGoogle Scholar
  42. 42.
    Biddinger SB, Kahn CR (2006) From mice to men: insights into the insulin resistance syndromes. Annu Rev Physiol 68:123–158PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag Italia 2012

Authors and Affiliations

  • L. Nasarre
    • 1
  • O. Juan-Babot
    • 1
  • P. Gastelurrutia
    • 2
  • A. Llucia-Valldeperas
    • 2
  • L. Badimon
    • 1
  • A. Bayes-Genis
    • 2
  • V. Llorente-Cortés
    • 1
  1. 1.Cardiovascular Research CenterCSIC-ICCC, IIB-Sant Pau, Hospital de la Santa Creu i Sant Pau, UABBarcelonaSpain
  2. 2.ICREC Research ProgramFundació Institut d’Investigació en Ciències de la Salut Germans Trias i Pujol (IGTP)BadalonaSpain

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