Cell and Tissue Research

, Volume 348, Issue 1, pp 71–80 | Cite as

Very-low-density lipoprotein mediates transcriptional regulation of aldosterone synthase in human adrenocortical cells through multiple signaling pathways

  • Sarama Saha
  • Stefan R. Bornstein
  • Juergen Graessler
  • Steffi Kopprasch
Regular Article

Abstract

Diabetic dyslipidemia is characterized by increased circulatory very-low-density lipoprotein (VLDL) levels. Aldosterone, apart from its role in fluid and electrolyte homeostasis, has also been implicated in insulin resistance and myocardial fibrosis. The impact of VLDL as a potential risk factor for aldosterone-mediated cardiovascular injury in diabetes mellitus, however, remains to be investigated. We have therefore studied native and modified VLDL-mediated steroidogenesis and its underlying molecular mechanisms in human adrenocortical carcinoma cells, NCI H295R. Native VLDL (natVLDL), isolated from healthy volunteers, was subjected to in vitro modification with glucose (200 mmol/l) or sodium hypochlorite (1.5 mmol/l) for preparation of glycoxidized and oxidized VLDL, respectively. VLDL treatment induced steroidogenesis in both a concentration- and time-dependent manner. Native and glycoxidized VLDL (50 μg/ml) were almost two-fold more potent in adrenocortical aldosterone release than angiotensin II (100 nmol/l). These forms of VLDL significantly augmented transcriptional regulation of aldosterone synthase (Cyp11B2), partially through scavenger receptor class B type I, as evident from the effect of BLT-1. In contrast to glycoxidized VLDL, oxidized VLDL significantly attenuated the stimulatory effect of natVLDL on adrenocortical hormone synthesis. Moreover, treatment with specific pharmacological inhibitors (H89, U0126, AG490) provided supporting evidence that VLDL, irrespective of modification, presumably recruited PKA, ERK1/2 and Jak-2 for steroid hormone release through modulation of Cyp11B2 mRNA level. In conclusion, this study demonstrates a novel insight into intracellular mechanism of VLDL-mediated aldosterone synthesis through transcriptional regulation of steroidogenic acute regulatory protein (StAR) and Cyp11B2 expression in human adrenocortical carcinoma cell line.

Keywords

VLDL Aldosterone MAP kinase Janus kinase Aldosterone synthase 

Notes

Acknowledgement

The authors would like to thank Martina Kohl, Sigrid Nitzsche and Eva Schubert for their excellent technical support and Kathy Eisenhofer for her careful reading of the manuscript. This work was supported by the Deutsche Forschungsgemeinschaft (KFO 252 to SRB).

References

  1. Adiels M, Taskinen MR, Packard C, Caslake MJ, Soro-Paavonen A, Westerbacka J, Vehkavaara S, Häkkinen A, Olofsson SO, Yki-Järvinen H, Borén J (2006) Overproduction of large VLDL particles is driven by increased liver fat content in man. Diabetologia 49:755–765PubMedCrossRefGoogle Scholar
  2. Adiels M, Olofsson SO, Taskinen MR, Borén J (2008) Overproduction of very low-density lipoproteins is the hallmark of the dyslipidemia in the metabolic syndrome. Arterioscler Thromb Vasc Biol 28:1225–1236PubMedCrossRefGoogle Scholar
  3. Ansurudeen I, Pietzsch J, Graessler J, Ehrhart-Bornstein M, Saha S, Bornstein SR, Kopprasch S (2010) Modulation of adrenal aldosterone release by oxidative modification of low-density lipoprotein. Am J Hypertens 23(10):1061–1068PubMedCrossRefGoogle Scholar
  4. Birkenkamp KU, Tuyt LML, Lummen C, Wierenga ATJ, Kruijer W, Vellenga W (2000) The p38 MAP kinase inhibitor SB203580 enhances nuclear factor-kappa B transcriptional activity by a non-specific effect upon the ERK pathway. Br J Pharmacol 131(1):99–107PubMedCrossRefGoogle Scholar
  5. Braun A, Trigatti BL, Post MJ, Sato K, Simons M, Edelberg JM, Rosenberg RD, Schrenzel M, Krieger M (2002) Loss of SR-BI expression leads to the early onset of occlusive atherosclerotic coronary artery disease, spontaneous myocardial infarctions, severe cardiac dysfunction, and premature death in apolipoprotein E–deficient mice. Circ Res 90:270–276PubMedCrossRefGoogle Scholar
  6. Brunzell JD, Davidson M, Furberg CD, Goldberg RB, Howard BV, Stein JH, Witztum JL (2008) Lipoprotein management in patients with cardiometabolic risk. Diabetes Care 31(4):811–822PubMedCrossRefGoogle Scholar
  7. Calvo D, Gómez-Coronado D, Suárez Y, Lasunción MA, Vega MA (1998) Human CD36 is a high affinity receptor for the native lipoproteins HDL, LDL, and VLDL. J Lipid Res 39:777–788PubMedGoogle Scholar
  8. Capponi AM (2002) Regulation of cholesterol supply for mineralocorticoid biosynthesis. Trends Endocrinol Metab 13(3):118–121PubMedCrossRefGoogle Scholar
  9. Cushley RJ, Okon M (2002) NMR studies of lipoprotein structure. Annu Rev Biophys Biomol Struct 31:177–206PubMedCrossRefGoogle Scholar
  10. Dinkel RE, Barrett PHR, Demant T, Parhofer KG (2006) In-vivo metabolism of VLDL-apolipoprotein-B, -CIII and -E in normolipidemic subjects. Nutr Metab Cardiovasc Dis 16:215–221PubMedCrossRefGoogle Scholar
  11. Frias MA, James RW, Wicht CG, Lang U (2009) Native and reconstituted HDL activate Stat3 in ventricular cardiomyocytes via ERK1/2: role of sphingosine-1-phosphate. Cardiovasc Res 82:313–323PubMedCrossRefGoogle Scholar
  12. Graessler J, Pietzsch J, Westendorf T, Julius U, Bornstein SR, Kopprasch S (2007) Glycoxidised LDL isolated from subjects with impaired glucose tolerance increases CD36 and peroxisome proliferator–activator receptor γ gene expression in macrophages. Diabetologia 50:1080–1088PubMedCrossRefGoogle Scholar
  13. Gwynne JT, Hess B (1980) The role of high density lipoproteins in rat adrenal cholesterol metabolism and steroidogenesis. J Biol Chem 255(22):10875–10883PubMedGoogle Scholar
  14. Higashijima M, Nawata H, Kato K, Ibayashi H (1987) Studies on lipoprotein and adrenal steroidogenesis: I. Roles of low density lipoprotein- and high density lipoprotein-cholesterol in steroid production in cultured human adrenocortical cells. Endocrinol Jpn 34(5):635–645PubMedCrossRefGoogle Scholar
  15. Hoekstra M, Korporaal SJA, Li Z, Zhao Y, Eck MV, Berkel TJCV (2010) Plasma lipoproteins are required for both basal and stress-induced adrenal glucocorticoid synthesis and protection against endotoxemia in mice. Am J Physiol Endocrinol Metab 299(6):E1038–E1043PubMedCrossRefGoogle Scholar
  16. Hu J, Zhang Z, Shen WJ, Azhar S (2010) Cellular cholesterol delivery, intracellular processing and utilization for biosynthesis of steroid hormones. Nutr Metab 7(47):1–25Google Scholar
  17. Kannel WB, Vasan RS (2009) Triglycerides as vascular risk factors: new epidemiologic insights. Curr Opin Cardiol 24(4):345–350PubMedCrossRefGoogle Scholar
  18. Kraemer FB (2007) Adrenal cholesterol utilization. Mol Cell Endocrinol 265–266:42–45PubMedCrossRefGoogle Scholar
  19. Krug AW, Ehrhart-Bornstein M (2008) Aldosterone and metabolic syndrome: is increased aldosterone in metabolic syndrome patients an additional risk factor? Hypertension 51:1252–1258PubMedCrossRefGoogle Scholar
  20. Laemmly UK (1970) Cleavage of structural proteins during the assembly of the head of bacteriophage T4. Nature 227:680–685CrossRefGoogle Scholar
  21. Levine RL, Garland D, Oliver CN, Amici A, Climent I, Lenz AG, Ahn BW, Shaltiel S, Stadtman ER (1990) Determination of carbonyl content in oxidatively modified proteins. Methods Enzymol 186:464–478PubMedCrossRefGoogle Scholar
  22. Li J, Feltzer RE, Dawson KL, Hudson EA, Clark BJ (2003) Janus Kinase 2 and calcium are required for angiotensinII-dependent activation of steroidogenic acute regulatory protein transcription in H295R human adrenocortical cells. J Biol Chem 278(52):52355–52362PubMedCrossRefGoogle Scholar
  23. Maeba R, Shimasaki H, Ueta N (1994) Conformational changes in oxidized LDL recognized by mouse peritoneal macrophages. Biochim Biophys Acta 1215:79–86PubMedGoogle Scholar
  24. Nieland TJF, Chroni A, Fitzgerald ML, Maliga Z, Zannis VI, Kirchhausen T, Krieger M (2004) Cross-inhibition of SR-BI- and ABCA1-mediated cholesterol transport by the small molecules BLT-4 and glyburide. J Lipid Res 45:1256–1265PubMedCrossRefGoogle Scholar
  25. Nofer JR, Fobker M, Höbbel G, Voss R, Wolinska I, Tepel M, Zidek W, Junker R, Seedorf U, von Eckardstein A, Assmann G, Walter M (2000) Activation of phosphatidylinositol-specific phospholipase C by HDL-associated lysosphingolipid: involvement in mitogenesis but not in cholesterol efflux. Biochemistry 39:15199–15207PubMedCrossRefGoogle Scholar
  26. Papadopoulos V, Baraldi M, Guilarte TR, Knudsen TB, Lacapere JJ, Lindemann P, Norenberg MD, Nutt D, Weizman A, Zhang MR, Gavish M (2006) Translocator protein (18kDa): new nomenclature for the peripheral-type benzodiazepine receptor based on its structure and molecular´function. Trends Pharmacol Sci 27:402–409PubMedCrossRefGoogle Scholar
  27. Pietzsch J, Subat S, Nitzsche S, Leonhardt W, Schentke KU, Hanefeld M (1995) Very fast ultracentrifugation of serum lipoproteins: influence on lipoprotein separation and composition. Biochim Biophys Acta 1254:77–88PubMedGoogle Scholar
  28. Quinn SJ, Williams GH (1988) Regulation of aldosterone secretion. Annu Rev Physiol 50:409–426PubMedCrossRefGoogle Scholar
  29. Richards JS (2001) New signaling pathways for hormones and cyclic adenosine 3',5'-monophosphate action in endocrine cells. Mol Endocrinol 15(2):209–218PubMedCrossRefGoogle Scholar
  30. Sachinidis A, Kettenhofen R, Seewald S, Gouni-Berthold I, Schmitz U, Seul C, Ko Y, Vetter H (1999) Evidence that lipoproteins are carriers of bioactive factors. Arterioscler Thromb Vasc Biol 19(10):2412–2421PubMedCrossRefGoogle Scholar
  31. Schmitt JM, Stork PJ (2002) Gα and Gβγ require distinct Src-dependent pathways to activate Rap1 and Ras. J Biol Chem 277:43024–43032PubMedCrossRefGoogle Scholar
  32. Stillemark-Billton P, Beck C, Borén J, Olofsson SO (2005) Relation of the size and intracellular sorting of apoB to the formation of VLDL 1 and VLDL 2. J Lipid Res 46:104–114PubMedCrossRefGoogle Scholar
  33. Xing Y, Cohen A, Rothblat G, Sankaranarayanan S, Weibel G, Royer L, Francone OL, Rainey WE (2011) Aldosterone production in human adrenocortical cells is stimulated by high-density lipoprotein 2 (HDL2) through increased expression of aldosterone aynthase (CYP11B2). Endocrinology 152(3):751–763PubMedCrossRefGoogle Scholar
  34. Yagi K (1976) A simple fluorometric assay for lipoperoxide in blood plasma. Biochem Med 15:212–216PubMedCrossRefGoogle Scholar
  35. Zheng X, Bollag WB (2003) AngII induces transient phospholipase D activity in the H295R glomerulosa cell model. Mol Cell Endocrinol 206(1–2):113–122PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag 2012

Authors and Affiliations

  • Sarama Saha
    • 1
  • Stefan R. Bornstein
    • 1
  • Juergen Graessler
    • 1
  • Steffi Kopprasch
    • 1
  1. 1.Department of Internal Medicine III, Carl Gustav Carus Medical SchoolTechnical University of DresdenDresdenGermany

Personalised recommendations