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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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.
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.
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.
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.
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.
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.
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.
Navab M, Van Lenten BJ, Reddy ST, Fogelman AM. High-density lipoprotein and the dynamics of atherosclerotic lesions. Circulation. 2001;104:2386–7.
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.
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.
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.
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.
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.
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.
Trougakos IP, Gonos ES. Clusterin/apolipoprotein J in human aging and cancer. Int J Biochem Cell Biol. 2002;34:1430–48.
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.
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.
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.
Schrijvers EM, Koudstaal PJ, Hofman A, Breteler MM. Plasma clusterin and the risk of Alzheimer disease. JAMA. 2011;305:1322–6.
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.
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.
de Silva HV, Harmony JA, Stuart WD, Gil CM, Robbins J. Apolipoprotein J: structure and tissue distribution. Biochemistry. 1990;29:5380–9.
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.
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.
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.
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.
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.
Wilson MR, Easterbrook-Smith SB. Clusterin is a secreted mammalian chaperone. Trends Biochem Sci. 2000;25:95–8.
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.
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.
Thomas-Salgar S, Millis AJ. Clusterin expression in differentiating smooth muscle cells. J Biol Chem. 1994;269:17879–85.
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.
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.
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.
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.
Henderson B, Pockley AG. Proteotoxic stress and circulating cell stress proteins in the cardiovascular diseases. Cell Stress Chaperones. 2012;17:303–11.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
Madamanchi NR, Vendrov A, Runge MS. Oxidative stress and vascular disease. Arterioscler Thromb Vasc Biol. 2005;25:29–38.
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.
Johnstone RW, Licht JD. Histone deacetylase inhibitors in cancer therapy: is transcription the primary target? Cancer Cell. 2003;4:13–8.
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.
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.
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.
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.
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.
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.
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.
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.
Levitan I, Volkov S, Subbaiah PV. Oxidized LDL: diversity, patterns of recognition, and pathophysiology. Antioxid Redox Signal. 2010;13:39–75.
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.
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.
Ammar H, Closset JL. Clusterin activates survival through the phosphatidylinositol 3-kinase/Akt pathway. J Biol Chem. 2008;283:12851–61.
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.
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.
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.
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.
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.
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.
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.
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.
McMurray JJ, Pfeffer MA. Heart failure. Lancet. 2005;365:1877–89.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
Friedman JM, Halaas JL. Leptin and the regulation of body weight in mammals. Nature. 1998;395:763–70.
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.
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.
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.
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.
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.
Bertram L, Tanzi RE. Genome-wide association studies in Alzheimer’s disease. Hum Mol Genet. 2009;18:R137–45.
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.
Tanzi RE, Moir RD, Wagner SL. Clearance of Alzheimer’s Abeta peptide: the many roads to perdition. Neuron. 2004;43:605–8.
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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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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DOI: https://doi.org/10.1007/s11154-013-9275-3