The adipokine chemerin and its receptor, chemokine-like receptor 1 (Cmklr1), are associated with insulin resistance and nonalcoholic fatty liver disease (NAFLD), which covers a broad spectrum of liver diseases, ranging from simple steatosis to nonalcoholic steatohepatitis (NASH). It is possible that chemerin and/or Cmklr1 exert their effects on these disorders through inflammation, but so far the data have been controversial. To gain further insight into this matter, we studied the effect of whole-body Cmklr1 deficiency on insulin resistance and NAFLD. In view of the primary role of macrophages in hepatic inflammation, we also transplanted bone marrow from Cmklr1 knock-out (Cmklr1-/-) mice and wild type (WT) mice into low-density lipoprotein receptor knock-out (Ldlr-/-) mice, a mouse model for NASH. All mice were fed a high fat, high cholesterol diet containing 21% fat from milk butter and 0.2% cholesterol for 12 weeks. Insulin resistance was assessed by an oral glucose tolerance test, an insulin tolerance test, and by measurement of plasma glucose and insulin levels. Liver pathology was determined by measuring hepatic inflammation, fibrosis, lipid accumulation and the NAFLD activity score (NAS). Whole-body Cmklr1 deficiency did not affect body weight gain or food intake. In addition, we observed no differences between WT and Cmklr1-/- mice for hepatic inflammatory and fibrotic gene expression, immune cell infiltration, lipid accumulation or NAS. In line with this, we detected no differences in insulin resistance. In concordance with whole-body Cmklr1 deficiency, the absence of Cmklr1 in bone marrow-derived cells in Ldlr-/- mice did not affect their insulin resistance or liver pathology. Our results indicate that Cmklr1 is not involved in the pathogenesis of insulin resistance or NAFLD. Thus, we recommend that the associations reported between Cmklr1 and insulin resistance or NAFLD should be interpreted with caution.
References
[1]
Blachier M, Leleu H, Peck-Radosavljevic M, Valla DC, Roudot-Thoraval F (2013) The burden of liver disease in europe: A review of available epidemiological data. J Hepatol 58: 593–608.
[2]
Cohen JC, Horton JD, Hobbs HH (2011) Human fatty liver disease: Old questions and new insights. Science 332: 1519–1523.
[3]
Wittamer V, Franssen JD, Vulcano M, Mirjolet JF, Le Poul E, et al. (2003) Specific recruitment of antigen-presenting cells by chemerin, a novel processed ligand from human inflammatory fluids. J Exp Med 198: 977–985.
[4]
Graham KL, Zabel BA, Loghavi S, Zuniga LA, Ho PP, et al. (2009) Chemokine-like receptor-1 expression by central nervous system-infiltrating leukocytes and involvement in a model of autoimmune demyelinating disease. J Immunol 183: 6717–6723.
[5]
Luangsay S, Wittamer V, Bondue B, De Henau O, Rouger L, et al. (2009) 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 183: 6489–6499.
[6]
Bondue B, Vosters O, de Nadai P, Glineur S, De Henau O, et al. (2011) ChemR23 dampens lung inflammation and enhances anti-viral immunity in a mouse model of acute viral pneumonia. PLoS Pathog 7: e1002358.
[7]
Bozaoglu K, Bolton K, McMillan J, Zimmet P, Jowett J, et al. (2007) Chemerin is a novel adipokine associated with obesity and metabolic syndrome. Endocrinology 148: 4687–4694.
[8]
Bozaoglu K, Segal D, Shields KA, Cummings N, Curran JE, et al. (2009) Chemerin is associated with metabolic syndrome phenotypes in a mexican-american population. J Clin Endocrinol Metab 94: 3085–3088.
[9]
Fatima SS, Bozaoglu K, Rehman R, Alam F, Memon AS (2013) Elevated chemerin levels in Pakistani men: An interrelation with metabolic syndrome phenotypes. PLoS One 8: e57113.
[10]
Kukla M, Zwirska-Korczala K, Hartleb M, Waluga M, Chwist A, et al. (2010) Serum chemerin and vaspin in non-alcoholic fatty liver disease. Scand J Gastroenterol 45: 235–242.
[11]
Sell H, Divoux A, Poitou C, Basdevant A, Bouillot JL, et al. (2010) Chemerin correlates with markers for fatty liver in morbidly obese patients and strongly decreases after weight loss induced by bariatric surgery. J Clin Endocrinol Metab 95: 2892–2896.
[12]
Deng Y, Wang H, Lu Y, Liu S, Zhang Q, et al. (2013) Identification of chemerin as a novel FXR target gene down-regulated in the progression of nonalcoholic steatohepatitis. Endocrinology 154: 1794–1801.
[13]
Docke S, Lock JF, Birkenfeld AL, Hoppe S, Lieske S, et al. (2013) Elevated hepatic chemerin mRNA expression in human non-alcoholic fatty liver disease. Eur J Endocrinol 169: 547–557.
[14]
Wanninger J, Bauer S, Eisinger K, Weiss TS, Walter R, et al. (2012) Adiponectin upregulates hepatocyte CMKLR1 which is reduced in human fatty liver. Mol Cell Endocrinol 349: 248–254.
[15]
Ernst MC, Haidl ID, Zuniga LA, Dranse HJ, Rourke JL, et al. (2012) Disruption of the chemokine-like receptor-1 (CMKLR1) gene is associated with reduced adiposity and glucose intolerance. Endocrinology 153: 672–682.
[16]
Rouger L, Denis GR, Luangsay S, Parmentier M (2013) ChemR23 knockout mice display mild obesity but no deficit in adipocyte differentiation. J Endocrinol 219: 279–289.
[17]
Zoetelief J, Broerse JJ, Davies RW, Octave-Prignot M, Rezvani M, et al. (2001) Protocol for X-ray dosimetry in radiobiology. Int J Radiat Biol 77: 817–835.
[18]
Bligh EG, Dyer WJ (1959) A rapid method of total lipid extraction and purification. Can J Biochem Physiol 37: 911–917.
[19]
Kleiner DE, Brunt EM, Van Natta M, Behling C, Contos MJ, et al. (2005) Design and validation of a histological scoring system for nonalcoholic fatty liver disease. Hepatology 41: 1313–1321.
[20]
Goralski KB, McCarthy TC, Hanniman EA, Zabel BA, Butcher EC, et al. (2007) Chemerin, a novel adipokine that regulates adipogenesis and adipocyte metabolism. J Biol Chem 282: 28175–28188.
[21]
Barnea G, Strapps W, Herrada G, Berman Y, Ong J, et al. (2008) The genetic design of signaling cascades to record receptor activation. Proc Natl Acad Sci U S A 105: 64–69.
[22]
Zabel BA, Nakae S, Zuniga L, Kim JY, Ohyama T, et al. (2008) Mast cell-expressed orphan receptor CCRL2 binds chemerin and is required for optimal induction of IgE-mediated passive cutaneous anaphylaxis. J Exp Med 205: 2207–2220.
[23]
Ernst MC, Issa M, Goralski KB, Sinal CJ (2010) Chemerin exacerbates glucose intolerance in mouse models of obesity and diabetes. Endocrinology 151: 1998–2007.
[24]
Becker M, Rabe K, Lebherz C, Zugwurst J, Goke B, et al. (2010) Expression of human chemerin induces insulin resistance in the skeletal muscle but does not affect weight, lipid levels, and atherosclerosis in LDL receptor knockout mice on high-fat diet. Diabetes 59: 2898–2903.
[25]
Wouters K, van Gorp PJ, Bieghs V, Gijbels MJ, Duimel H, et al. (2008) Dietary cholesterol, rather than liver steatosis, leads to hepatic inflammation in hyperlipidemic mouse models of nonalcoholic steatohepatitis. Hepatology 48: 474–486.
[26]
Bieghs V, Van Gorp PJ, Wouters K, Hendrikx T, Gijbels MJ, et al. (2012) LDL receptor knock-out mice are a physiological model particularly vulnerable to study the onset of inflammation in non-alcoholic fatty liver disease. PLoS One 7: e30668.
[27]
Crespo J, Cayon A, Fernandez-Gil P, Hernandez-Guerra M, Mayorga M, et al. (2001) Gene expression of tumor necrosis factor alpha and TNF-receptors, p55 and p75, in nonalcoholic steatohepatitis patients. Hepatology 34: 1158–1163.
[28]
Abiru S, Migita K, Maeda Y, Daikoku M, Ito M, et al. (2006) Serum cytokine and soluble cytokine receptor levels in patients with non-alcoholic steatohepatitis. Liver Int 26: 39–45.
[29]
Catalan V, Gomez-Ambrosi J, Rodriguez A, Ramirez B, Rotellar F, et al. (2013) Increased levels of chemerin and its receptor, chemokine-like receptor-1, in obesity are related to inflammation: Tumor necrosis factor-alpha stimulates mRNA levels of chemerin in visceral adipocytes from obese patients. Surg Obes Relat Dis 9: 306–314.
[30]
Parlee SD, Ernst MC, Muruganandan S, Sinal CJ, Goralski KB (2010) Serum chemerin levels vary with time of day and are modified by obesity and tumor necrosis factor-{alpha}. Endocrinology 151: 2590–2602.
[31]
Parlee SD, McNeil JO, Muruganandan S, Sinal CJ, Goralski KB (2012) Elastase and tryptase govern TNFalpha-mediated production of active chemerin by adipocytes. PLoS One 7: e51072.
[32]
Buechler C, Wanninger J, Neumeier M (2011) Adiponectin, a key adipokine in obesity related liver diseases. World J Gastroenterol 17: 2801–2811.
[33]
Bondue B, Wittamer V, Parmentier M (2011) Chemerin and its receptors in leukocyte trafficking, inflammation and metabolism. Cytokine Growth Factor Rev 22: 331–338.
[34]
Arita M, Bianchini F, Aliberti J, Sher A, Chiang N, et al. (2005) Stereochemical assignment, antiinflammatory properties, and receptor for the omega-3 lipid mediator resolvin E1. J Exp Med 201: 713–722.
[35]
Gonzalez-Periz A, Horrillo R, Ferre N, Gronert K, Dong B, et al. (2009) Obesity-induced insulin resistance and hepatic steatosis are alleviated by omega-3 fatty acids: A role for resolvins and protectins. FASEB J 23: 1946–1957.
