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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

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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 (R 2 = 0.50, P = 0.01 and R 2 = 0.44, P = 0.03, respectively) and epicardial LRP1 also correlated with plasma glucose levels (R 2 = 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.

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References

  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 44:127–133

    Article  CAS  PubMed  Google Scholar 

  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 91:4689–4695

    Article  PubMed  Google Scholar 

  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 30:850–856

    Article  PubMed  Google Scholar 

  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 88:5163–5168

    Article  CAS  PubMed  Google Scholar 

  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 108:2460–2466

    Article  PubMed  Google Scholar 

  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):1

    Article  Google Scholar 

  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 102:1602–1607

    Article  PubMed  Google Scholar 

  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 157:203–209

    Article  CAS  PubMed  Google Scholar 

  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–H209

    Article  CAS  PubMed  Google Scholar 

  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 52:1793–1799

    Article  PubMed  Google Scholar 

  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 50:894–902

    Article  CAS  PubMed  Google Scholar 

  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 94:469–479

    Article  CAS  PubMed  Google Scholar 

  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 277:10037–10043

    Article  CAS  PubMed  Google Scholar 

  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 21:1488–1493

    Article  CAS  PubMed  Google Scholar 

  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 268:974–981

    CAS  PubMed  Google Scholar 

  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 278:11945–11953

    Article  CAS  PubMed  Google Scholar 

  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 117:3271–3282

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  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 106:3104–3110

    Article  PubMed  Google Scholar 

  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 359:950–960

    Article  PubMed  Google Scholar 

  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 213:458–468

    Article  CAS  PubMed  Google Scholar 

  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 78:581–589

    Article  CAS  PubMed  Google Scholar 

  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 49:771–780

    Article  CAS  PubMed  Google Scholar 

  23. Bligh EG, Dyer WJ (1959) A rapid method of total lipid extraction and purification. Can J Biochem Physiol 37:911–917

    Article  CAS  PubMed  Google Scholar 

  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 28:88–136

    Google Scholar 

  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) 36:422–430

    Article  CAS  Google Scholar 

  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 220:223–230

    Article  CAS  PubMed  Google Scholar 

  27. Harmancey R, Wilson CR, Taegtmeyer H (2008) Adaptation and maladaptation of the heart in obesity. Hypertension 52:181–187

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  28. Sell H, Dietze-Schroeder D, Eckel J (2006) The adipocyte-myocyte axis in insulin resistance. Trends Endocrinol Metab 17:416–422

    Article  CAS  PubMed  Google Scholar 

  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 10:160

    Google Scholar 

  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 31:1411–1420

    Article  CAS  PubMed  Google Scholar 

  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:e7422

    Article  PubMed Central  PubMed  Google Scholar 

  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:e24783

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  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 264:10133–10138

    CAS  PubMed  Google Scholar 

  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 285:104–114

    Article  CAS  PubMed  Google Scholar 

  35. Bogan JS (2012) Regulation of glucose transporter translocation in health and diabetes. Annu Rev Biochem 81:507–532

    Article  CAS  PubMed  Google Scholar 

  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 308:283–290

    Article  CAS  PubMed  Google Scholar 

  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 146:3286–3294

    Article  CAS  PubMed  Google Scholar 

  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 284:30049–30057

    Article  CAS  PubMed  Google Scholar 

  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 11:200–208

    Article  CAS  PubMed  Google Scholar 

  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 314:814–824

    Article  CAS  PubMed  Google Scholar 

  41. Kahn SE, Hull RL, Utzschneider KM (2006) Mechanisms linking obesity to insulin resistance and type 2 diabetes. Nature 444:840–846

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

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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.

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Authors and Affiliations

  1. Cardiovascular Research Center, CSIC-ICCC, IIB-Sant Pau, Hospital de la Santa Creu i Sant Pau, UAB, Sant Antoni Mª Claret, 167, 08025, Barcelona, Spain

    L. Nasarre, O. Juan-Babot, L. Badimon & V. Llorente-Cortés

  2. ICREC Research Program, Fundació Institut d’Investigació en Ciències de la Salut Germans Trias i Pujol (IGTP), Badalona, Spain

    P. Gastelurrutia, A. Llucia-Valldeperas & A. Bayes-Genis

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  1. L. Nasarre
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Correspondence to V. Llorente-Cortés.

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Communicated by Guido Pozza.

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Nasarre, L., Juan-Babot, O., Gastelurrutia, P. et al. 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. Acta Diabetol 51, 23–30 (2014). https://doi.org/10.1007/s00592-012-0436-8

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