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The physiological roles of apolipoprotein J/clusterin in metabolic and cardiovascular diseases

Reviews in Endocrine and Metabolic Disorders volume 15, pages 45–53 (2014)Cite this article

Abstract

Several isoforms of apolipoprotein J/clusterin (CLU) are encoded from a single gene located on chromosome 8 in humans. These isoforms are ubiquitously expressed in the tissues, and have been implicated in aging, neurodegenerative disorders, cancer progression, and metabolic/cardiovascular diseases including dyslipidemia, diabetes, atherosclerosis and myocardial infarction. The conventional secreted form of CLU (sCLU) is thought to be a component of high density lipoprotein-cholesterol. sCLU functions as a chaperone for misfolded proteins and it is thought to promote survival by reducing oxidative stress. Nuclear CLU, a truncated CLU formed by alternative splicing, is responsible for promoting apoptosis via a Bax-dependent pathway. There are putative regulatory sites in the promoter regions of CLU, which are occupied by transcription factors such as transforming growth factor (TGF)-β inhibitory element, activator protein-1, CLU-specific elements, and carbohydrate response element. However, the molecular mechanisms underlying the distinct roles of CLU in a variety of conditions remain unclear. Although the function of CLU in cancer or neurological disease has been studied intensively for three decades, physiological roles of CLU seem unexplored in the cardiovascular system and metabolic diseases. In this review, we will discuss general characteristics and regulations of CLU based on previous literature and assess the recent findings associated with its physiological roles in different tissues including the vasculature, heart, liver, kidney, adipose tissue, and brain.

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References

  1. Di Angelantonio E, Sarwar N, Perry P, Kaptoge S, Ray KK, Thompson A, et al. Major lipids, apolipoproteins, and risk of vascular disease. JAMA. 2009;302:1993–2000.

    PubMed  Article  Google Scholar 

  2. Forte TM, Subbanagounder G, Berliner JA, Blanche PJ, Clermont AO, Jia Z, et al. Altered activities of anti-atherogenic enzymes LCAT, paraoxonase, and platelet-activating factor acetylhydrolase in atherosclerosis-susceptible mice. J Lipid Res. 2002;43:477–85.

    CAS  PubMed  Article  Google Scholar 

  3. Hedrick CC, Thorpe SR, Fu MX, Harper CM, Yoo J, Kim SM, et al. Glycation impairs high-density lipoprotein function. Diabetologia. 2000;43:312–20.

    CAS  PubMed  Article  Google Scholar 

  4. Besler C, Heinrich K, Rohrer L, Doerries C, Riwanto M, Shih DM, et al. Mechanisms underlying adverse effects of HDL on eNOS-activating pathways in patients with coronary artery disease. J Clin Invest. 2011;121:2693–708.

    CAS  PubMed Central  PubMed  Article  Google Scholar 

  5. Navab M, Anantharamaiah GM, Reddy ST, Van Lenten BJ, Fogelman AM. HDL as a biomarker, potential therapeutic target, and therapy. Diabetes. 2009;58:2711–7.

    CAS  PubMed  Article  Google Scholar 

  6. Navab M, Berliner JA, Subbanagounder G, Hama S, Lusis AJ, Castellani LW, et al. HDL and the inflammatory response induced by LDL-derived oxidized phospholipids. Arterioscler Thromb Vasc Biol. 2001;21:481–8.

    CAS  PubMed  Article  Google Scholar 

  7. Getz GS, Wool GD, Reardon CA. HDL apolipoprotein-related peptides in the treatment of atherosclerosis and other inflammatory disorders. Curr Pharm Des. 2010;16:3173–84.

    CAS  PubMed Central  PubMed  Article  Google Scholar 

  8. Navab M, Van Lenten BJ, Reddy ST, Fogelman AM. High-density lipoprotein and the dynamics of atherosclerotic lesions. Circulation. 2001;104:2386–7.

    CAS  PubMed  Google Scholar 

  9. Troutt JS, Alborn WE, Mosior MK, Dai J, Murphy AT, Beyer TP, et al. An apolipoprotein A-I mimetic dose-dependently increases the formation of prebeta1 HDL in human plasma. J Lipid Res. 2008;49:581–7.

    CAS  PubMed  Article  Google Scholar 

  10. Fryirs MA, Barter PJ, Appavoo M, Tuch BE, Tabet F, Heather AK, et al. Effects of high-density lipoproteins on pancreatic beta-cell insulin secretion. Arterioscler Thromb Vasc Biol. 2010;30:1642–8.

    CAS  PubMed  Article  Google Scholar 

  11. Morgantini C, Imaizumi S, Grijalva V, Navab M, Fogelman AM, Reddy ST. Apolipoprotein A-I mimetic peptides prevent atherosclerosis development and reduce plaque inflammation in a murine model of diabetes. Diabetes. 2010;59:3223–8.

    CAS  PubMed  Article  Google Scholar 

  12. Morgantini C, Natali A, Boldrini B, Imaizumi S, Navab M, Fogelman AM, et al. Anti-inflammatory and antioxidant properties of HDLs are impaired in type 2 diabetes. Diabetes. 2011;60:2617–23.

    CAS  PubMed  Article  Google Scholar 

  13. Riwanto M, Rohrer L, Roschitzki B, Besler C, Mocharla P, Mueller M, et al. Altered activation of endothelial anti- and proapoptotic pathways by high-density lipoprotein from patients with coronary artery disease: role of high-density lipoprotein-proteome remodeling. Circulation. 2013;127:891–904.

    CAS  PubMed  Article  Google Scholar 

  14. Poon S, Easterbrook-Smith SB, Rybchyn MS, Carver JA, Wilson MR. Clusterin is an ATP-independent chaperone with very broad substrate specificity that stabilizes stressed proteins in a folding-competent state. Biochemistry. 2000;39:15953–60.

    CAS  PubMed  Article  Google Scholar 

  15. Trougakos IP, Gonos ES. Clusterin/apolipoprotein J in human aging and cancer. Int J Biochem Cell Biol. 2002;34:1430–48.

    CAS  PubMed  Article  Google Scholar 

  16. Wong P, Taillefer D, Lakins J, Pineault J, Chader G, Tenniswood M. Molecular characterization of human TRPM-2/clusterin, a gene associated with sperm maturation, apoptosis and neurodegeneration. Eur J Biochem. 1994;221:917–25.

    CAS  PubMed  Article  Google Scholar 

  17. Wong P, Pineault J, Lakins J, Taillefer D, Leger J, Wang C, et al. Genomic organization and expression of the rat TRPM-2 (clusterin) gene, a gene implicated in apoptosis. J Biol Chem. 1993;268:5021–31.

    CAS  PubMed  Google Scholar 

  18. Tycko B, Feng L, Nguyen L, Francis A, Hays A, Chung WY, et al. Polymorphisms in the human apolipoprotein-J/clusterin gene: ethnic variation and distribution in Alzheimer’s disease. Hum Genet. 1996;98:430–6.

    CAS  PubMed  Article  Google Scholar 

  19. Schrijvers EM, Koudstaal PJ, Hofman A, Breteler MM. Plasma clusterin and the risk of Alzheimer disease. JAMA. 2011;305:1322–6.

    CAS  PubMed  Article  Google Scholar 

  20. Lambert JC, Heath S, Even G, Campion D, Sleegers K, Hiltunen M, et al. Genome-wide association study identifies variants at CLU and CR1 associated with Alzheimer’s disease. Nat Genet. 2009;41:1094–9.

    CAS  PubMed  Article  Google Scholar 

  21. Harold D, Abraham R, Hollingworth P, Sims R, Gerrish A, Hamshere ML, et al. Genome-wide association study identifies variants at CLU and PICALM associated with Alzheimer’s disease. Nat Genet. 2009;41:1088–93.

    CAS  PubMed Central  PubMed  Article  Google Scholar 

  22. de Silva HV, Harmony JA, Stuart WD, Gil CM, Robbins J. Apolipoprotein J: structure and tissue distribution. Biochemistry. 1990;29:5380–9.

    PubMed  Article  Google Scholar 

  23. Jenne DE, Tschopp J. Molecular structure and functional characterization of a human complement cytolysis inhibitor found in blood and seminal plasma: identity to sulfated glycoprotein 2, a constituent of rat testis fluid. Proc Natl Acad Sci U S A. 1989;86:7123–7.

    CAS  PubMed Central  PubMed  Article  Google Scholar 

  24. Trougakos IP, Gonos ES. Regulation of clusterin/apolipoprotein J, a functional homologue to the small heat shock proteins, by oxidative stress in ageing and age-related diseases. Free Radic Res. 2006;40:1324–34.

    CAS  PubMed  Article  Google Scholar 

  25. Leskov KS, Araki S, Lavik JP, Gomez JA, Gama V, Gonos ES, et al. CRM1 protein-mediated regulation of nuclear clusterin (nCLU), an ionizing radiation-stimulated, Bax-dependent pro-death factor. J Biol Chem. 2011;286:40083–90.

    CAS  PubMed  Article  Google Scholar 

  26. Nizard P, Tetley S, Le Drean Y, Watrin T, Le Goff P, Wilson MR, et al. Stress-induced retrotranslocation of clusterin/ApoJ into the cytosol. Traffic. 2007;8:554–65.

    CAS  PubMed  Article  Google Scholar 

  27. Blaschuk O, Burdzy K, Fritz IB. Purification and characterization of a cell-aggregating factor (clusterin), the major glycoprotein in ram rete testis fluid. J Biol Chem. 1983;258:7714–20.

    CAS  PubMed  Google Scholar 

  28. Wilson MR, Easterbrook-Smith SB. Clusterin is a secreted mammalian chaperone. Trends Biochem Sci. 2000;25:95–8.

    CAS  PubMed  Article  Google Scholar 

  29. Michel D, Chatelain G, Herault Y, Brun G. The expression of the avian clusterin gene can be driven by two alternative promoters with distinct regulatory elements. Eur J Biochem. 1995;229:215–23.

    CAS  PubMed  Article  Google Scholar 

  30. Humphreys D, Hochgrebe TT, Easterbrook-Smith SB, Tenniswood MP, Wilson MR. Effects of clusterin overexpression on TNFalpha- and TGFbeta-mediated death of L929 cells. Biochemistry. 1997;36:15233–43.

    CAS  PubMed  Article  Google Scholar 

  31. Thomas-Salgar S, Millis AJ. Clusterin expression in differentiating smooth muscle cells. J Biol Chem. 1994;269:17879–85.

    CAS  PubMed  Google Scholar 

  32. Laping NJ, Morgan TE, Nichols NR, Rozovsky I, Young-Chan CS, Zarow C, et al. Transforming growth factor-beta 1 induces neuronal and astrocyte genes: tubulin alpha 1, glial fibrillary acidic protein and clusterin. Neuroscience. 1994;58:563–72.

    CAS  PubMed  Article  Google Scholar 

  33. Khan QE, Sehic A, Khuu C, Risnes S, Osmundsen H. Expression of Clu and Tgfb1 during murine tooth development: effects of in-vivo transfection with anti-miR-214. Eur J Oral Sci. 2013;121:303–12.

    CAS  PubMed  Article  Google Scholar 

  34. Donnelly TJ, Sievers RE, Vissern FL, Welch WJ, Wolfe CL. Heat shock protein induction in rat hearts. A role for improved myocardial salvage after ischemia and reperfusion? Circulation. 1992;85:769–78.

    CAS  PubMed  Article  Google Scholar 

  35. Marber MS, Mestril R, Chi SH, Sayen MR, Yellon DM, Dillmann WH. Overexpression of the rat inducible 70-kD heat stress protein in a transgenic mouse increases the resistance of the heart to ischemic injury. J Clin Invest. 1995;95:1446–56.

    CAS  PubMed Central  PubMed  Article  Google Scholar 

  36. Henderson B, Pockley AG. Proteotoxic stress and circulating cell stress proteins in the cardiovascular diseases. Cell Stress Chaperones. 2012;17:303–11.

    CAS  PubMed Central  PubMed  Article  Google Scholar 

  37. Yom CK, Woo HY, Min SY, Kang SY, Kim HS. Clusterin overexpression and relapse-free survival in breast cancer. Anticancer Res. 2009;29:3909–12.

    PubMed  Google Scholar 

  38. Ranney MK, Ahmed IS, Potts KR, Craven RJ. Multiple pathways regulating the anti-apoptotic protein clusterin in breast cancer. Biochim Biophys Acta. 2007;1772:1103–11.

    CAS  PubMed Central  PubMed  Article  Google Scholar 

  39. Wei L, Xue T, Wang J, Chen B, Lei Y, Huang Y, et al. Roles of clusterin in progression, chemoresistance and metastasis of human ovarian cancer. Int J Cancer. 2009;125:791–806.

    CAS  PubMed  Article  Google Scholar 

  40. Xie D, Sham JS, Zeng WF, Che LH, Zhang M, Wu HX, et al. Oncogenic role of clusterin overexpression in multistage colorectal tumorigenesis and progression. World J Gastroenterol. 2005;11:3285–9.

    CAS  PubMed  Google Scholar 

  41. July LV, Akbari M, Zellweger T, Jones EC, Goldenberg SL, Gleave ME. Clusterin expression is significantly enhanced in prostate cancer cells following androgen withdrawal therapy. Prostate. 2002;50:179–88.

    CAS  PubMed  Article  Google Scholar 

  42. Liu T, Liu PY, Tee AE, Haber M, Norris MD, Gleave ME, et al. Over-expression of clusterin is a resistance factor to the anti-cancer effect of histone deacetylase inhibitors. Eur J Cancer. 2009;45:1846–54.

    CAS  PubMed  Article  Google Scholar 

  43. Saad F, Hotte S, North S, Eigl B, Chi K, Czaykowski P, et al. Randomized phase II trial of Custirsen (OGX-011) in combination with docetaxel or mitoxantrone as second-line therapy in patients with metastatic castrate-resistant prostate cancer progressing after first-line docetaxel: CUOG trial P-06c. Clin Cancer Res. 2011;17:5765–73.

    CAS  PubMed  Article  Google Scholar 

  44. Laskin JJ, Nicholas G, Lee C, Gitlitz B, Vincent M, Cormier Y, et al. Phase I/II trial of custirsen (OGX-011), an inhibitor of clusterin, in combination with a gemcitabine and platinum regimen in patients with previously untreated advanced non-small cell lung cancer. J Thorac Oncol. 2012;7:579–86.

    CAS  PubMed  Article  Google Scholar 

  45. Kususda Y, Miyake H, Gleave ME, Fujisawa M. Clusterin inhibition using OGX-011 synergistically enhances antitumour activity of sorafenib in a human renal cell carcinoma model. Br J Cancer. 2012;106:1945–52.

    CAS  PubMed Central  PubMed  Article  Google Scholar 

  46. Chang YJ, Tai CJ, Kuo LJ, Wei PL, Liang HH, Liu TZ, et al. Glucose-regulated protein 78 (GRP78) mediated the efficacy to curcumin treatment on hepatocellular carcinoma. Ann Surg Oncol. 2011;18:2395–403.

    PubMed  Article  Google Scholar 

  47. Wang C, Jiang K, Gao D, Kang X, Sun C, Zhang Q, et al. Clusterin protects hepatocellular carcinoma cells from endoplasmic reticulum stress induced apoptosis through GRP78. PLoS One. 2013;8:e55981.

    CAS  PubMed Central  PubMed  Article  Google Scholar 

  48. Lee KB, Jeon JH, Choi I, Kwon OY, Yu K, You KH. Clusterin, a novel modulator of TGF-beta signaling, is involved in Smad2/3 stability. Biochem Biophys Res Commun. 2008;366:905–9.

    CAS  PubMed  Article  Google Scholar 

  49. Trougakos IP, Lourda M, Antonelou MH, Kletsas D, Gorgoulis VG, Papassideri IS, et al. Intracellular clusterin inhibits mitochondrial apoptosis by suppressing p53-activating stress signals and stabilizing the cytosolic Ku70-Bax protein complex. Clin Cancer Res. 2009;15:48–59.

    CAS  PubMed  Article  Google Scholar 

  50. Madamanchi NR, Vendrov A, Runge MS. Oxidative stress and vascular disease. Arterioscler Thromb Vasc Biol. 2005;25:29–38.

    CAS  PubMed  Google Scholar 

  51. Antonelou MH, Kriebardis AG, Stamoulis KE, Trougakos IP, Papassideri IS. Apolipoprotein J/Clusterin is a novel structural component of human erythrocytes and a biomarker of cellular stress and senescence. PLoS One. 2011;6:e26032.

    CAS  PubMed Central  PubMed  Article  Google Scholar 

  52. Johnstone RW, Licht JD. Histone deacetylase inhibitors in cancer therapy: is transcription the primary target? Cancer Cell. 2003;4:13–8.

    CAS  PubMed  Article  Google Scholar 

  53. Kim N, Yoo JC, Han JY, Hwang EM, Kim YS, Jeong EY, et al. Human nuclear clusterin mediates apoptosis by interacting with Bcl-XL through C-terminal coiled coil domain. J Cell Physiol. 2012;227:1157–67.

    CAS  PubMed  Article  Google Scholar 

  54. Valko M, Leibfritz D, Moncol J, Cronin MT, Mazur M, Telser J. Free radicals and antioxidants in normal physiological functions and human disease. Int J Biochem Cell Biol. 2007;39:44–84.

    CAS  PubMed  Article  Google Scholar 

  55. Daimon M, Oizumi T, Karasawa S, Kaino W, Takase K, Tada K, et al. Association of the clusterin gene polymorphisms with type 2 diabetes mellitus. Metabolism. 2011;60:815–22.

    CAS  PubMed  Article  Google Scholar 

  56. Han BH, DeMattos RB, Dugan LL, Kim-Han JS, Brendza RP, Fryer JD, et al. Clusterin contributes to caspase-3-independent brain injury following neonatal hypoxia-ischemia. Nat Med. 2001;7:338–43.

    CAS  PubMed  Article  Google Scholar 

  57. Leskov KS, Klokov DY, Li J, Kinsella TJ, Boothman DA. Synthesis and functional analyses of nuclear clusterin, a cell death protein. J Biol Chem. 2003;278:11590–600.

    CAS  PubMed  Article  Google Scholar 

  58. Lee DH, Ha JH, Kim Y, Bae KH, Park JY, Choi WS, et al. Interaction of a putative BH3 domain of clusterin with anti-apoptotic Bcl-2 family proteins as revealed by NMR spectroscopy. Biochem Biophys Res Commun. 2011;408:541–7.

    CAS  PubMed  Article  Google Scholar 

  59. Zong WX, Lindsten T, Ross AJ, MacGregor GR, Thompson CB. BH3-only proteins that bind pro-survival Bcl-2 family members fail to induce apoptosis in the absence of Bax and Bak. Genes Dev. 2001;15:1481–6.

    CAS  PubMed  Article  Google Scholar 

  60. Rahman ST, Merchant N, Haque T, Wahi J, Bhaheetharan S, Ferdinand KC, et al. The impact of lipoic acid on endothelial function and proteinuria in quinapril-treated diabetic patients with stage I hypertension: results from the QUALITY study. J Cardiovasc Pharmacol Ther. 2012;17:139–45.

    CAS  PubMed  Article  Google Scholar 

  61. Levitan I, Volkov S, Subbaiah PV. Oxidized LDL: diversity, patterns of recognition, and pathophysiology. Antioxid Redox Signal. 2010;13:39–75.

    CAS  PubMed  Article  Google Scholar 

  62. Navab M, Anantharamaiah GM, Reddy ST, Hama S, Hough G, Frank JS, et al. Oral small peptides render HDL antiinflammatory in mice and monkeys and reduce atherosclerosis in ApoE null mice. Circ Res. 2005;97:524–32.

    CAS  PubMed  Article  Google Scholar 

  63. Navab M, Anantharamaiah GM, Reddy ST, Hama S, Hough G, Grijalva VR, et al. Oral D-4F causes formation of pre-beta high-density lipoprotein and improves high-density lipoprotein-mediated cholesterol efflux and reverse cholesterol transport from macrophages in apolipoprotein E-null mice. Circulation. 2004;109:3215–20.

    CAS  PubMed  Article  Google Scholar 

  64. Ammar H, Closset JL. Clusterin activates survival through the phosphatidylinositol 3-kinase/Akt pathway. J Biol Chem. 2008;283:12851–61.

    CAS  PubMed  Article  Google Scholar 

  65. Miyata M, Biro S, Kaieda H, Eto H, Orihara K, Kihara T, et al. Apolipoprotein J/clusterin is induced in vascular smooth muscle cells after vascular injury. Circulation. 2001;104:1407–12.

    CAS  PubMed  Article  Google Scholar 

  66. Kim HJ, Yoo EK, Kim JY, Choi YK, Lee HJ, Kim JK, et al. Protective role of clusterin/apolipoprotein J against neointimal hyperplasia via antiproliferative effect on vascular smooth muscle cells and cytoprotective effect on endothelial cells. Arterioscler Thromb Vasc Biol. 2009;29:1558–64.

    CAS  PubMed  Article  Google Scholar 

  67. Franco DA, Truran S, Burciu C, Gutterman DD, Maltagliati A, Weissig V, et al. Protective role of clusterin in preserving endothelial function in AL amyloidosis. Atherosclerosis. 2012;225:220–3.

    CAS  PubMed Central  PubMed  Article  Google Scholar 

  68. Urbich C, Fritzenwanger M, Zeiher AM, Dimmeler S. Laminar shear stress upregulates the complement-inhibitory protein clusterin : a novel potent defense mechanism against complement-induced endothelial cell activation. Circulation. 2000;101:352–5.

    CAS  PubMed  Article  Google Scholar 

  69. Hamada N, Miyata M, Eto H, Ikeda Y, Shirasawa T, Akasaki Y, et al. Loss of clusterin limits atherosclerosis in apolipoprotein E-deficient mice via reduced expression of Egr-1 and TNF-alpha. J Atheroscler Thromb. 2011;18:209–16.

    CAS  PubMed  Article  Google Scholar 

  70. Chen YR, Chen CL, Pfeiffer DR, Zweier JL. Mitochondrial complex II in the post-ischemic heart: oxidative injury and the role of protein S-glutathionylation. J Biol Chem. 2007;282:32640–54.

    CAS  PubMed  Article  Google Scholar 

  71. Du Y, Navab M, Shen M, Hill J, Pakbin P, Sioutas C, et al. Ambient ultrafine particles reduce endothelial nitric oxide production via S-glutathionylation of eNOS. Biochem Biophys Res Commun. 2013;436:462–6.

    CAS  PubMed  Article  Google Scholar 

  72. Moxon JV, Padula MP, Clancy P, Emeto TI, Herbert BR, Norman PE, et al. Proteomic analysis of intra-arterial thrombus secretions reveals a negative association of clusterin and thrombospondin-1 with abdominal aortic aneurysm. Atherosclerosis. 2011;219:432–9.

    CAS  PubMed  Article  Google Scholar 

  73. McMurray JJ, Pfeffer MA. Heart failure. Lancet. 2005;365:1877–89.

    PubMed  Article  Google Scholar 

  74. Van Dijk A, Vermond RA, Krijnen PA, Juffermans LJ, Hahn NE, Makker SP, et al. Intravenous clusterin administration reduces myocardial infarct size in rats. Eur J Clin Invest. 2010;40:893–902.

    PubMed  Article  Google Scholar 

  75. Morales CR, Igdoura SA, Wosu UA, Boman J, Argraves WS. Low density lipoprotein receptor-related protein-2 expression in efferent duct and epididymal epithelia: evidence in rats for its in vivo role in endocytosis of apolipoprotein J/clusterin. Biol Reprod. 1996;55:676–83.

    CAS  PubMed  Article  Google Scholar 

  76. Postic C, Girard J. Contribution of de novo fatty acid synthesis to hepatic steatosis and insulin resistance: lessons from genetically engineered mice. J Clin Invest. 2008;118:829–38.

    CAS  PubMed Central  PubMed  Article  Google Scholar 

  77. Deng X, Yellaturu C, Cagen L, Wilcox HG, Park EA, Raghow R, et al. Expression of the rat sterol regulatory element-binding protein-1c gene in response to insulin is mediated by increased transactivating capacity of specificity protein 1 (Sp1). J Biol Chem. 2007;282:17517–29.

    CAS  PubMed  Article  Google Scholar 

  78. Horton JD, Bashmakov Y, Shimomura I, Shimano H. Regulation of sterol regulatory element binding proteins in livers of fasted and refed mice. Proc Natl Acad Sci U S A. 1998;95:5987–92.

    CAS  PubMed Central  PubMed  Article  Google Scholar 

  79. Seo HY, Kim MK, Jung YA, Jang BK, Yoo EK, Park KG, et al. Clusterin decreases hepatic SREBP-1c expression and lipid accumulation. Endocrinology. 2013;154:1722–30.

    CAS  PubMed  Article  Google Scholar 

  80. Kim G, Kim GH, Oh GS, Yoon J, Kim HW, Kim MS, et al. SREBP-1c regulates glucose-stimulated hepatic clusterin expression. Biochem Biophys Res Commun. 2011;408:720–5.

    CAS  PubMed  Article  Google Scholar 

  81. Rahmouni K, Morgan DA, Morgan GM, Mark AL, Haynes WG. Role of selective leptin resistance in diet-induced obesity hypertension. Diabetes. 2005;54:2012–8.

    CAS  PubMed  Article  Google Scholar 

  82. Harlan SM, Morgan DA, Agassandian K, Guo DF, Cassell MD, Sigmund CD, et al. Ablation of the leptin receptor in the hypothalamic arcuate nucleus abrogates leptin-induced sympathetic activation. Circ Res. 2011;108:808–12.

    CAS  PubMed Central  PubMed  Article  Google Scholar 

  83. Lin Z, Tian H, Lam KS, Lin S, Hoo RC, Konishi M, et al. Adiponectin mediates the metabolic effects of FGF21 on glucose homeostasis and insulin sensitivity in mice. Cell Metab. 2013;17:779–89.

    CAS  PubMed  Article  Google Scholar 

  84. Park S, Lu KT, Liu X, Chatterjee TK, Rudich SM, Weintraub NL, et al. Allele-specific expression of angiotensinogen in human subcutaneous adipose tissue. Hypertension. 2013;62:41–7.

    CAS  PubMed  Article  Google Scholar 

  85. Bajari TM, Strasser V, Nimpf J, Schneider WJ. A model for modulation of leptin activity by association with clusterin. FASEB J. 2003;17:1505–7.

    CAS  PubMed  Google Scholar 

  86. Friedman JM, Halaas JL. Leptin and the regulation of body weight in mammals. Nature. 1998;395:763–70.

    CAS  PubMed  Article  Google Scholar 

  87. Caro JF, Kolaczynski JW, Nyce MR, Ohannesian JP, Opentanova I, Goldman WH, et al. Decreased cerebrospinal-fluid/serum leptin ratio in obesity: a possible mechanism for leptin resistance. Lancet. 1996;348:159–61.

    CAS  PubMed  Article  Google Scholar 

  88. Gil SY, Youn BS, Byun K, Huang H, Namkoong C, Jang PG, et al. Clusterin and LRP2 are critical components of the hypothalamic feeding regulatory pathway. Nat Commun. 2013;4:1862.

    PubMed  Article  Google Scholar 

  89. Rosenberg ME, Girton R, Finkel D, Chmielewski D, Barrie 3rd A, Witte DP, et al. Apolipoprotein J/clusterin prevents a progressive glomerulopathy of aging. Mol Cell Biol. 2002;22:1893–902.

    CAS  PubMed Central  PubMed  Article  Google Scholar 

  90. Jung GS, Kim MK, Jung YA, Kim HS, Park IS, Min BH, et al. Clusterin attenuates the development of renal fibrosis. J Am Soc Nephrol. 2012;23:73–85.

    CAS  PubMed  Article  Google Scholar 

  91. Tuncdemir M, Ozturk M. The effects of ACE inhibitor and angiotensin receptor blocker on clusterin and apoptosis in the kidney tissue of streptozotocin-diabetic rats. J Mol Histol. 2008;39:605–16.

    CAS  PubMed  Article  Google Scholar 

  92. Bertram L, Tanzi RE. Genome-wide association studies in Alzheimer’s disease. Hum Mol Genet. 2009;18:R137–45.

    CAS  PubMed  Article  Google Scholar 

  93. Zlokovic BV, Martel CL, Matsubara E, McComb JG, Zheng G, McCluskey RT, et al. Glycoprotein 330/megalin: probable role in receptor-mediated transport of apolipoprotein J alone and in a complex with Alzheimer disease amyloid beta at the blood-brain and blood-cerebrospinal fluid barriers. Proc Natl Acad Sci U S A. 1996;93:4229–34.

    CAS  PubMed Central  PubMed  Article  Google Scholar 

  94. Tanzi RE, Moir RD, Wagner SL. Clearance of Alzheimer’s Abeta peptide: the many roads to perdition. Neuron. 2004;43:605–8.

    CAS  PubMed  Google Scholar 

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Acknowledgment

This work was supported by the National Research Foundation of Korea (NRF) grant funded by the Korean Ministry of Education (MOE)(2012R1A2A1A03670452), a grant of the Korea Health Technology R&D Project, Ministry of Health and Welfare, Republic of Korea (A111345), and supported by Kyungpook National University Research Fund, 2013.

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Affiliations

  1. Leading-edge Research Center for Drug Discovery and Development for Diabetes and Metabolic Disease, Kyungpook National University Hospital, Daegu, Republic of Korea

    S. Park

  2. Department of Physiology and Biophysics, University of Mississippi Medical Center, Jackson, MS, USA

    K. W. Mathis

  3. Department of Internal Medicine, Kyungpook National University School of Medicine, Kyungpook National University, 50 Samduk-2Ga, Jung-Gu, Daegu, Republic of Korea, 700-721

    I. K. Lee

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Park, S., Mathis, K.W. & Lee, I.K. The physiological roles of apolipoprotein J/clusterin in metabolic and cardiovascular diseases. Rev Endocr Metab Disord 15, 45–53 (2014). https://doi.org/10.1007/s11154-013-9275-3

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Keywords

  • Atherosclerosis
  • Clusterin-deficient mice
  • Diabetes
  • High density cholesterol
  • Oxidative stress