The role of chemerin in human disease
Magdalena Stojek 1Abstract
Adipose tissue is not merely a storage depot of triacylglycerols but also a major endocrine organ. Its cells, including adipocytes, synthesize and secrete a range of biologically active molecules termed adipokines. Adipokines that display the properties of cytokines are often called adipocytokines. In recent years there has been increasing interest in a new adipokine called chemerin. Chemerin is a protein synthesized mostly by the adipose tissue and the liver as inactive pre-pro-chemerin. After the intracellular hydrolytic cutting off of the 20-amino-acid N-terminal polypeptide, it is secreted into the bloodstream as inactive pro-chemerin. Biologically active chemerin is then derived from pro-chemerin after cleavage of the C-terminal fragment by serum proteases involved in inflammation, coagulation and fibrinolysis. Proteolytic cleavage leads to formation of several chemerin-derived peptides, both biologically active (often with opposing functions) and inactive.Within the last decade, there has been a growing number of publications regarding the role of chemerin in human disease. It seems to be implicated in the inflammatory response, metabolic syndrome, cardiovascular disease and alimentary tract disorders. The article presents the most recent information on the role of chemerin in human disease, and specifically alimentary tract disorders. The available evidence suggests that chemerin is an important link between adipose tissue mass, metabolic processes, the immune system and inflammation, and therefore plays a major role in human pathophysiology.
References
- 1. Adrych K., Stojek M., Smoczynski M., Sledzinski T., Sylwia S.W., Swierczynski J.: Increased serum chemerin concentration in patients with chronic pancreatitis. Dig. Liver Dis., 2012; 44: 393‑397
Google Scholar - 2. Albanesi C., Scarponi C., Pallotta S., Daniele R., Bosisio D., Madon‑ na S., Fortugno P., Gonzalvo‑Feo S., Franssen J.D., Parmentier M., De Pità O., Girolomoni G., Sozzani S.: Chemerin expression marks early psoriatic skin lesions and correlates with plasmacytoid dendritic cell recruitment. J. Exp. Med., 2009; 206: 249‑258
Google Scholar - 3. Banas M., Zabieglo K., Kasetty G., Kapinska‑Mrowiecka M., Borow‑ czyk J., Drukala J., Murzyn K., Zabel B.A., Butcher E.C., Schroeder J.M., Schmidtchen A., Cichy J.: Chemerin is an antimicrobial agent in human epidermis. PLoS One, 2013; 8: e58709
Google Scholar - 4. Bauer S., Bala M., Kopp A., Eisinger K., Schmid A., Schneider S., Neumeier M., Buechler C.: Adipocyte chemerin release is induced by insulin without being translated to higher levels in vivo. Eur. J. Clin. Invest., 2012; 42: 1213‑1220
Google Scholar - 5. Bauer S., Wanninger J., Schmidhofer S., Weigert J., Neumeier M., Dorn C., Hellerbrand C., Zimara N., Schäffler A., Aslanidis C., Buechler C.: Sterol regulatory element‑binding protein 2 (SREBP2) activation after excess triglyceride storage induces chemerin in hypertrophic adipocytes. Endocrinology, 2011; 152: 26‑35
Google Scholar - 6. Blüher M., Mantzoros C.S.: From leptin to other adipokines in health and disease: facts and expectations at the beginning of the 21st century. Metabolism, 2015; 64: 131‑145
Google Scholar - 7. Bozaoglu K., Bolton K., McMillan J., Zimmet P., Jowett J., Collier G., Walder K., Segal D.: Chemerin is a novel adipokine associated with obesity and metabolic syndrome. Endocrinology, 2007; 148: 4687‑4694
Google Scholar - 8. Bozaoglu K., Segal D., Shields K.A., Cummings N., Curran J.E., Co‑ muzzie A.G., Mahaney M.C., Rainwater D.L., VandeBerg J.L., MacCluer J.W., Collier G., Blangero J., Walder K., Jowett J.B.: Chemerin is associ‑ ated with metabolic syndrome phenotypes in a Mexican‑American population. J. Clin. Endocrinol. Metab., 2009; 94: 3085‑3088
Google Scholar - 9. Cash J.L., Bass M.D., Campbell J., Barnes M., Kubes P., Martin P.: Resolution mediator chemerin15 reprograms the wound microen‑ vironment to promote repair and reduce scarring. Curr. Biol., 2014; 24: 1406‑1414
Google Scholar - 10. Cash J.L., Bena S., Headland S.E., McArthur S., Brancaleone V., Perretti M.: Chemerin15 inhibits neutrophil‑mediated vascular in‑ flammation and myocardial ischemia‑reperfusion injury through ChemR23. EMBO Rep., 2013; 14: 999‑1007
Google Scholar - 11. ] Cash J.L., Hart R., Russ A., Dixon J.P., Colledge W.H., Doran J., Hen‑ drick A.G., Carlton M.B., Greaves D.R.: Synthetic chemerin‑derived peptides suppress inflammation through ChemR23. J. Exp. Med., 2008; 205: 767‑775
Google Scholar - 12. Chu S.H., Lee M.K., Ahn K.Y., Im J.A., Park M.S., Lee D.C., Jeon J.Y., Lee J.W.: Chemerin and adiponectin contribute reciprocally to metabolic syndrome. PLoS One, 2012; 7: e34710
Google Scholar - 13. De Palma G., Castellano G., Del Prete A., Sozzani S., Fiore N., Loverre A., Parmentier M., Gesualdo L., Grandaliano G., Schena F.P.: The possible role of ChemR23/Chemerin axis in the recruitment of dendritic cells in lupus nephritis. Kidney Int., 2011; 79: 1228‑1235
Google Scholar - 14. Demoor T., Bracke K.R., Dupont L.L., Plantinga M., Bondue B., Roy M.O., Lannoy V., Lambrecht B.N., Brusselle G.G., Joos G.F.: The role of ChemR23 in the induction and resolution of cigarette smoke‑induced inflammation. J. Immunol., 2011; 186: 5457‑5467
Google Scholar - 15. Dong B., Ji W., Zhang Y.: Elevated serum chemerin levels are as‑ sociated with the presence of coronary artery disease in patients with metabolic syndrome. Intern. Med., 2011; 50: 1093‑1097
Google Scholar - 16. Doyle J.R., Krishnaji S.T., Zhu G., Xu Z.Z., Heller D., Ji R.R., Levy B.D., Kumar K., Kopin A.S.: Development of a membrane‑anchored chemer‑ in receptor agonist as a novel modulator of allergic airway inflam‑ mation and neuropathic pain. J. Biol. Chem., 2014; 289: 13385‑13396
Google Scholar - 17. Du X.Y., Leung L.L.: Proteolytic regulatory mechanism of chemerin bioactivity. Acta Biochim. Biophys. Sin., 2009; 41: 973‑979
Google Scholar - 18. Du X.Y., Zabel B.A., Myles T., Allen S.J., Handel T.M., Lee P.P., Butcher E.C., Leung L.L.: Regulation of chemerin bioactivity by plasma carboxypeptidase N, carboxypeptidase B (activated throm‑ bin‑activable fibrinolysis inhibitor), and platelets. J. Biol. Chem., 2009; 284: 751‑758
Google Scholar - 19. Ernst M.C., Haidl I.D., Zúñiga L.A., Dranse H.J., Rourke J.L., Za‑ bel B.A., Butcher E.C., Sinal C.J.: Disruption of the chemokine‑like receptor‑1 (CMKLR1) gene is associated with reduced adiposity and glucose intolerance. Endocrinology, 2012; 153: 672‑682
Google Scholar - 20. Gao X., Mi S., Zhang F., Gong F., Lai Y., Gao F., Zhang X., Wang L., Tao H.: Association of chemerin mRNA expression in human epi‑ cardial adipose tissue with coronary atherosclerosis. Cardiovasc. Diabetol., 2011; 10: 87
Google Scholar - 21. Goralski K.B., McCarthy T.C., Hanniman E.A., Zabel B.A., Butch‑ er E.C., Parlee S.D., Muruganandan S., Sinal C.J.: Chemerin, a novel adipokine that regulates adipogenesis and adipocyte metabolism. J. Biol. Chem., 2007; 282: 28175‑28188
Google Scholar - 22. Graham K.L., Zabel B.A., Loghavi S., Zuniga L.A., Ho P.P., Sobel R.A., Butcher E.C.: Chemokine‑like receptor‑1 expression by central nervous system‑infiltrating leukocytes and involvement in a mod‑ el of autoimmune demyelinating disease. J. Immunol., 2009; 183: 6717‑6723
Google Scholar - 23. Guillabert A., Wittamer V., Bondue B., Godot V., Imbault V., Par‑ mentier M., Communi D.: Role of neutrophil proteinase 3 and mast cell chymase in chemerin proteolytic regulation. J. Leukoc. Biol., 2008; 84: 1530‑1538
Google Scholar - 24. Hah Y.J., Kim N.K., Kim M.K., Kim H.S., Hur S.H., Yoon H.J., Kim Y.N., Park K.G.: Relationship between chemerin levels and cardio‑ metabolic parameters and degree of coronary stenosis in Korean patients with coronary artery disease. Diabetes Metab. J., 2011; 35: 248‑254
Google Scholar - 25. Imai K., Takai K., Hanai T., Shiraki M., Suzuki Y., Hayashi H., Naiki T., Nishigaki Y., Tomita E., Shimizu M., Moriwaki H.: Impact of serum chemerin levels on liver functional reserves and platelet counts in patients with hepatocellular carcinoma. Int. J. Mol. Sci., 2014; 15: 11294‑11306
Google Scholar - 26. Kaneko K., Miyabe Y., Takayasu A., Fukuda S., Miyabe C., Ebisawa M., Yokoyama W., Watanabe K., Imai T., Muramoto K., Terashima Y., Sugihara T., Matsushima K., Miyasaka N., Nanki T.: Chemerin acti‑ vates fibroblast‑like synoviocytes in patients with rheumatoid ar‑ thritis. Arthritis Res. Ther., 2011; 13: R158
Google Scholar - 27. Karcz K., Thomusch O.: Principles of Metabolic Surgery. Spring‑ er‑Verlag Berlin Heidelberg, 2012
Google Scholar - 28. Karlsson C., Lindell K., Ottosson M., Sjöström L., Carlsson B., Carlsson L.M.: Human adipose tissue expresses angiotensinogen and enzymes required for its conversion to angiotensin II. J. Clin. Endocrinol. Metab., 1998; 83: 3925‑3929
Google Scholar - 29. Kaur J., Adya R., Tan B.K., Chen J., Randeva H.S.: Identification of chemerin receptor (ChemR23) in human endothelial cells: chemer‑ in‑induced endothelial angiogenesis. Biochem. Biophys. Res. Com‑ mun., 2010; 391: 1762‑1768
Google Scholar - 30. Kern P.A., Ranganathan S., Li C., Wood L., Ranganathan G.: Adi‑ pose tissue tumor necrosis factor and interleukin‑6 expression in human obesity and insulin resistance. Am. J. Physiol. Endocrinol. Metab., 2001; 280: E745‑E751
Google Scholar - 31. Kralisch S., Weise S., Sommer G., Lipfert J., Lossner U., Bluher M., Stumvoll M., Fasshauer M.: Interleukin‑1β induces the novel adipo‑ kine chemerin in adipocytes in vitro. Regul. Pept., 2009; 154: 102‑106
Google Scholar - 32. Kukla M., Zwirska‑Korczala K., Gabriel A., Waluga M., Wara‑ komska I., Szczygiel B., Berdowska A., Mazur W., Wozniak‑Grygiel E., Kryczka W.: Chemerin, vaspin and insulin resistance in chronic hepatitis C. J. Viral Hepat., 2010; 17: 661‑667
Google Scholar - 33. Kukla M., Zwirska‑Korczala K., Hartleb M., Waluga M., Chwist A., Kajor M., Ciupinska‑Kajor M., Berdowska A., Wozniak‑Grygiel E., Buldak R.: Serum chemerin and vaspin in non‑alcoholic fatty liver disease. Scand. J. Gastroenterol., 2010; 45: 235‑242
Google Scholar - 34. Kumar J.D., Holmberg C., Kandola S., Steele I., Hegyi P., Tiszlavicz L., Jenkins R., Beynon R.J., Peeney D., Giger O.T., Alqahtani A., Wang T.C., Charvat T.T., Penfold M., Dockray G.J., Varro A.: Increased ex‑ pression of chemerin in squamous esophageal cancer myofibro‑ blasts and role in recruitment of mesenchymal stromal cells. PLoS One, 2014; 9: e104877
Google Scholar - 35. Lehrke M., Becker A., Greif M., Stark R., Laubender R.P., von Ziegler F., Lebherz C., Tittus J., Reiser M., Becker C., Göke B., Leber A.W., Parhofer K.G., Broedl U.C.: Chemerin is associated with mark‑ ers of inflammation and components of the metabolic syndrome but does not predict coronary atherosclerosis. Eur. J. Endocrinol., 2009; 161: 339‑344
Google Scholar - 36. Lin W., Chen Y.L., Jiang L., Chen J.K.: Reduced expression of chemerin is associated with a poor prognosis and a lowed infiltra‑ tion of both dendritic cells and natural killer cells in human hepa‑ tocellular carcinoma. Clin. Lab., 2011; 57: 879‑885
Google Scholar - 37. Luangsay S., Wittamer V., Bondue B., De Henau O., Rouger L., Brait M., Franssen J.D., de Nadai P., Huaux F., Parmentier M.: Mouse ChemR23 is expressed in dendritic cell subsets and macrophages, and mediates an anti‑inflammatory activity of chemerin in a lung disease model. J. Immunol., 2009; 183: 6489‑6499
Google Scholar - 38. Mariani F., Roncucci L.: Chemerin/chemR23 axis in inflamma‑ tion onset and resolution. Inflamm. Res., 2015; 64: 85‑95
Google Scholar - 39. Muruganandan S., Parlee S.D., Rourke J.L., Ernst M.C., Goralski K.B., Sinal C.J.: Chemerin, a novel peroxisome proliferator‑activated receptor g (PPARg) target gene that promotes mesenchymal stem cell adipogenesis. J. Biol. Chem., 2011; 286: 23982‑23995
Google Scholar - 40. Nagpal S., Patel S., Jacobe H., DiSepio D., Ghosn C., Malhotra M., Teng M., Duvic M., Chandraratna R.A.: Tazarotene‑induced gene 2 (TIG2), a novel retinoid‑responsive gene in skin. J. Invest. Derma‑ tol., 1997; 109: 91‑95
Google Scholar - 41. Nickoloff B.J.: Skin innate immune system in psoriasis: friend or foe? J. Clin. Invest., 1999; 104: 1161‑1164
Google Scholar - 42. Parlee S.D., Ernst M.C., Muruganandan S., Sinal C.J., Goralski K.B.: Serum chemerin levels vary with time of day and are modi‑ fied by obesity and tumor necrosis factor‑α. Endocrinology, 2010; 151: 2590‑2602
Google Scholar - 43. Parolini S., Santoro A., Marcenaro E., Luini W., Massardi L., Fac‑ chetti F., Communi D., Parmentier M., Majorana A., Sironi M., Tabel‑ lini G., Moretta A., Sozzani S.: The role of chemerin in the colocaliza‑ tion of NK and dendritic cell subsets into inflamed tissues. Blood, 2007; 109: 3625‑3632
Google Scholar - 44. Ress C., Tschoner A., Engl J., Klaus A., Tilg H., Ebenbichler C.F., Patsch J.R., Kaser S.: Effect of bariatric surgery on circulating chemerin levels. Eur. J. Clin. Invest., 2010; 40: 277‑280
Google Scholar - 45. Rourke J.L., Dranse H.J., Sinal C.J.: Towards an integrative ap‑ proach to understanding the role of chemerin in human health and disease. Obes. Rev., 2013; 14: 245‑262
Google Scholar - 46. Rutkowski P., Sledzinski T., Zielinska H., Lizakowski S., Goyke E., Szrok‑Wojtkiewicz S., Swierczynski J., Rutkowski B.: Decrease of se‑ rum chemerin concentration in patients with end stage renal disease after successful kidney transplantation. Regul. Pept., 2012; 173: 55‑59
Google Scholar - 47. Saremi A., Shavandi N., Parastesh M., Daneshmand H.: Twelve‑week aerobic training decreases chemerin level and im‑ proves cardiometabolic risk factors in overweight and obese men. Asian J. Sports Med., 2010; 1: 151‑158
Google Scholar - 48. Sell H., Divoux A., Poitou C., Basdevant A., Bouillot J.L., Bedossa P., Tordjman J., Eckel J., Clément K.: Chemerin correlates with mark‑ ers for fatty liver in morbidly obese patients and strongly decreases after weight loss induced by bariatric surgery. J. Clin. Endocrinol. Metab., 2010; 95: 2892‑2896
Google Scholar - 49. Sell H., Laurencikiene J., Taube A., Eckardt K., Cramer A., Hor‑ righs A., Arner P., Eckel J.: Chemerin is a novel adipocyte‑derived factor inducing insulin resistance in primary human skeletal muscle cells. Diabetes, 2009; 58: 2731‑2740
Google Scholar - 50. Shin H.Y., Lee D.C., Chu S.H., Jeon J.Y., Lee M.K., Im J.A., Lee J.W.: Chemerin levels are positively correlated with abdominal visceral fat accumulation. Clin. Endocrinol., 2012; 77: 47‑50
Google Scholar - 51. Silaghi A., Piercecchi‑Marti M.D., Grino M., Leonetti G., Alessi M.C., Clement K., Dadoun F., Dutour A.: Epicardial adipose tissue ex‑ tent: relationship with age, body fat distribution, and coronaropathy. Obesity, 2008; 16: 2424‑2430
Google Scholar - 52. Sledzinski T., Korczynska J., Hallmann A., Kaska L., Procz‑ ko‑Markuszewska M., Stefaniak T., Sledzinski M., Swierczynski J.: The increase of serum chemerin concentration is mainly associated with the increase of body mass index in obese, non‑diabetic subjects. J. Endocrinol. Invest., 2013; 36: 428‑434
Google Scholar - 53. Stejskal D., Karpisek M., Hanulova Z., Svestak M.: Chemerin is an independent marker of the metabolic syndrome in a Caucasian population ‑ a pilot study. Biomed. Pap. Med. Fac. Univ. Palacky Olo‑ mouc Czech Repub., 2008; 152: 217‑221
Google Scholar - 54. Stelmanska E., Sledzinski T., Turyn J., Presler M., Korczynska J., Swierczynski J.: Chemerin gene expression is regulated by food restriction and food restriction‑refeeding in rat adipose tissue but not in liver. Regul. Pept., 2013; 181: 22‑29
Google Scholar - 55. Takahashi M., Okimura Y., Iguchi G., Nishizawa H., Yamamoto M., Suda K., Kitazawa R., Fujimoto W., Takahashi K., Zolotaryov F.N., Hong K.S., Kiyonari H., Abe T., Kaji H., Kitazawa S., Kasuga M., Chi‑ hara K., Takahashi Y.: Chemerin regulates β‑cell function in mice. Sci. Rep., 2011; 1: 123
Google Scholar - 56. Taleb S., Lacasa D., Bastard J.P., Poitou C., Cancello R., Pelloux V., Viguerie N., Benis A., Zucker J.D., Bouillot J.L., Coussieu C., Bas‑ devant A., Langin D., Clement K.: Cathepsin S, a novel biomarker of adiposity: relevance to atherogenesis. FASEB J., 2005; 19: 1540‑1542
Google Scholar - 57. Toczyłowski K., Gruca M., Baranowski M.: Tkanka tłuszczowa na‑ sierdziowa. Znaczenie fizjologiczne oraz rola w patofizjologii chorób serca. Postępy Hig. Med. Dośw., 2013; 67: 584‑593
Google Scholar - 58. Trayhurn P., Wood I.S.: Signalling role of adipose tissue: adi‑ pokines and inflammation in obesity. Biochem. Soc. Trans., 2005; 33: 1078‑1081
Google Scholar - 59. Vermi W., Riboldi E., Wittamer V., Gentili F., Luini W., Marrelli S., Vecchi A., Franssen J.D., Communi D., Massardi L., Sironi M., Man‑ tovani A., Parmentier M., Facchetti F., Sozzani S.: Role of ChemR23 in directing the migration of myeloid and plasmacytoid dendritic cells to lymphoid organs and inflamed skin. J. Exp. Med., 2005; 201: 509‑515
Google Scholar - 60. Wang C., Wu W.K., Liu X., To K.F., Chen G.G., Yu J., Ng E.K.: In‑ creased serum chemerin level promotes cellular invasiveness in gastric cancer: a clinical and experimental study. Peptides, 2014; 51: 131‑138
Google Scholar - 61. Weigert J., Neumeier M., Wanninger J., Filarsky M., Bauer S., Wi‑ est R., Farkas S., Scherer M.N., Schäffler A., Aslanidis C., Schölmerich J., Buechler C.: Systemic chemerin is related to inflammation rather than obesity in type 2 diabetes. Clin. Endocrinol., 2010; 72: 342‑348
Google Scholar - 62. Weigert J., Obermeier F., Neumeier M., Wanninger J., Filarsky M., Bauer S., Aslanidis C., Rogler G., Ott C., Schäffler A., Schölmerich J., Buechler C.: Circulating levels of chemerin and adiponectin are higher in ulcerative colitis and chemerin is elevated in Crohn’s dis‑ ease. Inflamm. Bowel Dis., 2010; 16: 630‑637
Google Scholar - 63. Weisberg S.P., McCann D., Desai M., Rosenbaum M., Leibel R.L., Ferrante A.W.Jr.: Obesity is associated with macrophage accumula‑ tion in adipose tissue. J. Clin. Invest., 2003; 112: 1796‑1808
Google Scholar - 64. Wittamer V., Franssen J.D., Vulcano M., Mirjolet J.F., Le Poul E., Migeotte I., Brézillon S., Tyldesley R., Blanpain C., Detheux M., Man‑ tovani A., Sozzani S., Vassart G., Parmentier M., Communi D.: Spe‑ cific recruitment of antigen‑presenting cells by chemerin, a novel processed ligand from human inflammatory fluids. J. Exp. Med., 2003; 198: 977‑985
Google Scholar - 65. Xiaotao L., Xiaoxia Z., Yue X., Liye W.: Serum chemerin levels are associated with the presence and extent of coronary artery disease. Coron. Artery Dis., 2012; 23: 412‑416
Google Scholar - 66. Yan Q., Zhang Y., Hong J., Gu W., Dai M., Shi J., Zhai Y., Wang W., Li X., Ning G.: The association of serum chemerin level with risk of co‑ ronary artery disease in Chinese adults. Endocrine, 2012; 41: 281‑288
Google Scholar - 67. Yoshimura T., Oppenheim J.J.: Chemerin reveals its chimeric nature. J. Exp. Med., 2008; 205: 2187‑2190
Google Scholar - 68. Zabel B.A., Allen S.J., Kulig P., Allen J.A., Cichy J., Handel T.M., Butcher E.C.: Chemerin activation by serine proteases of the co‑ agulation, fibrinolytic, and inflammatory cascades. J. Biol. Chem., 2005; 280: 34661‑34666
Google Scholar - 69. Zhao L., Yang W., Yang X., Lin Y., Lv J., Dou X., Luo Q., Dong J., Chen Z., Chu Y., He R.: Chemerin suppresses murine allergic asthma by inhibiting CCL2 production and subsequent airway recruitment of inflammatory dendritic cells. Allergy, 2014; 69: 763‑774
Google Scholar