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Christa Buechler - One of the best experts on this subject based on the ideXlab platform.
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Serum Chemerin Does Not Differentiate Colorectal Liver Metastases from Hepatocellular Carcinoma
International journal of molecular sciences, 2019Co-Authors: Susanne Feder, Thomas S. Weiss, Doris Schacherer, A Kandulski, Christa BuechlerAbstract:The chemoattractant adipokine Chemerin is related to the metabolic syndrome, which is a risk factor for different cancers. Recent studies provide evidence that Chemerin is an important molecule in colorectal cancer (CRC) and hepatocellular carcinoma (HCC). Serum Chemerin is high in CRC patients and low in HCC patients and may serve as a differential diagnostic marker for HCC and liver metastases from CRC. To this end, serum Chemerin was measured in 36 patients with CRC metastases, 32 patients with HCC and 49 non-tumor patients by ELISA. Chemerin serum protein levels were, however, similar in the three cohorts. Serum Chemerin was higher in hypertensive than normotensive tumor patients but not controls. Cancer patients with hypercholesterolemia or hyperuricemia also had increased serum Chemerin. When patients with these comorbidities were excluded from the calculation, Chemerin was higher in CRC than HCC patients but did not differ from controls. Chemerin did not correlate with the tumor markers carcinoembryonic antigen, carbohydrate antigen 19-9 and alpha-fetoprotein in both cohorts and was not changed with tumor-node-metastasis stage in HCC. Chemerin was not associated with hepatic fat, liver inflammation and fibrosis. To conclude, systemic Chemerin did not discriminate between CRC metastases and HCC. Comorbidities among tumor patients were linked with elevated systemic Chemerin.
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Chemerin Isoforms and Activity in Obesity
International journal of molecular sciences, 2019Co-Authors: Christa Buechler, Elisabeth M. Haberl, Susanne Feder, Charalampos AslanidisAbstract:Overweight and adiposity are risk factors for several diseases, like type 2 diabetes and cancer. White adipose tissue is a major source for adipokines, comprising a diverse group of proteins exerting various functions. Chemerin is one of these proteins whose systemic levels are increased in obesity. Chemerin is involved in different physiological and pathophysiological processes and it regulates adipogenesis, insulin sensitivity, and immune response, suggesting a vital role in metabolic health. The majority of serum Chemerin is biologically inert. Different proteases are involved in the C-terminal processing of Chemerin and generate diverse isoforms that vary in their activity. Distribution of Chemerin variants was analyzed in adipose tissues and plasma of lean and obese humans and mice. The Tango bioassay, which is suitable to monitor the activation of the beta-arrestin 2 pathway, was used to determine the ex-vivo activation of Chemerin receptors by systemic Chemerin. Further, the expression of the Chemerin receptors was analyzed in adipose tissue, liver, and skeletal muscle. Present investigations assume that increased systemic Chemerin in human obesity is not accompanied by higher biologic activity. More research is needed to fully understand the pathways that control Chemerin processing and Chemerin signaling.
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Chemerin in a Mouse Model of Non-alcoholic Steatohepatitis and Hepatocarcinogenesis.
Anticancer research, 2018Co-Authors: Elisabeth M. Haberl, Christopher J. Sinal, Rebekka Pohl, Lisa Rein-fischboeck, Susanne Feder, Christa BuechlerAbstract:Background/aim Non-alcoholic steatohepatitis (NASH) is a risk factor for hepatocellular carcinoma (HCC). The adipokine Chemerin protects from HCC and is reduced in human HCC. In this study, Chemerin expression was analyzed in a murine model of NASH-HCC. Materials and methods Serum and hepatic Chemerin, and ex vivo Chemerin receptor activation were monitored in NASH and NASH-HCC in mice fed a low-methionine diet deficient in choline after initiation of tumors by injection of diethylnitrosamine. Results In non-tumorous liver tissues, the extent of hepatic steatosis, and the levels of proteins regulating hepatic lipids and liver fibrosis were similar in NASH and NASH-associated HCC. Systemic and hepatic Chemerin, and Chemerin receptor activation were not changed in HCC. Liver tumors only developed in diethylnitrosamine-injected mice and their number was increased in NASH. Chemerin protein was induced in liver in NASH, but was unchanged in HCC tissues. Conclusion Hepatic and serum Chemerin and ex vivo analyzed Chemerin receptor activation do not differ in murine NASH-associated HCC when compared to NASH. Hepatic tumors still develop despite high endogenous levels of serum and liver Chemerin protein.
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Reduced serum Chemerin in patients with more severe liver cirrhosis.
Experimental and molecular pathology, 2015Co-Authors: Kristina Eisinger, Sabrina Krautbauer, Thomas S. Weiss, Reiner Wiest, Christa BuechlerAbstract:Chemerin is a well-established modulator of immune cell function and its serum levels are induced in inflammatory diseases. Liver cirrhosis is associated with inflammation which is aggravated by portal hypertension. The objective of this study was to evaluate whether Chemerin is induced in patients with more severe liver cirrhosis and portal hypertension. Chemerin has been measured by ELISA in the portal venous serum (PVS), systemic venous serum (SVS) and hepatic venous serum (HVS) of 45 patients with liver cirrhosis. Chemerin is higher in HVS compared to PVS in accordance with our recently published finding. SVS, HVS and PVS Chemerin decline in patients with more advanced liver injury defined by the CHILD-PUGH score. Hepatic Chemerin has been determined in a small cohort and is similarly expressed in normal and cirrhotic liver. MELD score and serum markers of liver and kidney function do not correlate with Chemerin. There is a positive correlation of Chemerin in all compartments with Quick prothrombin time and of SVS Chemerin with systolic blood pressure. PVS Chemerin is induced in patients with modest/massive ascites but this does not translate into higher HVS and SVS levels. Chemerin is not associated with variceal size. Reduction of portal pressure by transjugular intrahepatic portosystemic shunt does not affect Chemerin levels. These data show that low Chemerin in patients with more severe liver cirrhosis is associated with reduced Quick prothrombin time.
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Chemerin is highly expressed in hepatocytes and is induced in non alcoholic steatohepatitis liver
Experimental and Molecular Pathology, 2013Co-Authors: Sabrina Krautbauer, Kristina Eisinger, Thomas S. Weiss, Josef Wanninger, Yvonne Hader, Michael Beck, Andrea Kopp, Andreas Schmid, C Dorn, Christa BuechlerAbstract:Chemerin is a recently described adipokine whose adipose tissue and serum levels are increased in obesity. Chemerin is expressed in the liver, and here, expression of Chemerin has been studied in liver cells and in non-alcoholic fatty liver disease (NAFLD) which is more often found in obesity. Chemerin is shown to be highly expressed in primary human hepatocytes (PHH) whereas hepatic stellate cells (HSC) produce only low levels of this protein. In mice fed a high fat diet hepatic Chemerin mRNA but not protein is increased. Chemerin protein is comparably expressed in the liver of control animals and ob/ob mice. Rodents fed a Paigen diet or methionine-choline deficient diet (MCD) develop non-alcoholic steatohepatitis (NASH), and liver Chemerin protein tends to be higher in the first and is significantly increased in the latter. Of note, MCD fed mice have similar serum Chemerin levels as the respective control animals despite lower body weight. In human fatty liver and NASH liver Chemerin mRNA also tends to be induced. Cytokines like TNF and adipokines with an established role in NASH do not considerably affect PHH Chemerin protein. The antidiabetic drug metformin reduces cellular and soluble Chemerin in PHH as has already been described in adipose tissue. In conclusion current data show that primary human hepatocytes are a major source of hepatic Chemerin and increased liver Chemerin in NASH may even contribute to systemic levels.
Christopher J. Sinal - One of the best experts on this subject based on the ideXlab platform.
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More Than an Adipokine: The Complex Roles of Chemerin Signaling in Cancer.
International journal of molecular sciences, 2019Co-Authors: Kerry B. Goralski, Ashley E. Jackson, Brendan T. Mckeown, Christopher J. SinalAbstract:Chemerin is widely recognized as an adipokine, with diverse biological roles in cellular differentiation and metabolism, as well as a leukocyte chemoattractant. Research investigating the role of Chemerin in the obesity–cancer relationship has provided evidence both for pro- and anti-cancer effects. The tumor-promoting effects of Chemerin primarily involve direct effects on migration, invasion, and metastasis as well as growth and proliferation of cancer cells. Chemerin can also promote tumor growth via the recruitment of tumor-supporting mesenchymal stromal cells and stimulation of angiogenesis pathways in endothelial cells. In contrast, the majority of evidence supports that the tumor-suppressing effects of Chemerin are immune-mediated and result in a shift from immunosuppressive to immunogenic cell populations within the tumor microenvironment. Systemic Chemerin and Chemerin produced within the tumor microenvironment may contribute to these effects via signaling through CMKLR1 (Chemerin1), GPR1 (Chemerin2), and CCLR2 on target cells. As such, inhibition or activation of Chemerin signaling could be beneficial as a therapeutic approach depending on the type of cancer. Additional studies are required to determine if obesity influences cancer initiation or progression through increased adipose tissue production of Chemerin and/or altered Chemerin processing that leads to changes in Chemerin signaling in the tumor microenvironment.
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Chemerin in a Mouse Model of Non-alcoholic Steatohepatitis and Hepatocarcinogenesis.
Anticancer research, 2018Co-Authors: Elisabeth M. Haberl, Christopher J. Sinal, Rebekka Pohl, Lisa Rein-fischboeck, Susanne Feder, Christa BuechlerAbstract:Background/aim Non-alcoholic steatohepatitis (NASH) is a risk factor for hepatocellular carcinoma (HCC). The adipokine Chemerin protects from HCC and is reduced in human HCC. In this study, Chemerin expression was analyzed in a murine model of NASH-HCC. Materials and methods Serum and hepatic Chemerin, and ex vivo Chemerin receptor activation were monitored in NASH and NASH-HCC in mice fed a low-methionine diet deficient in choline after initiation of tumors by injection of diethylnitrosamine. Results In non-tumorous liver tissues, the extent of hepatic steatosis, and the levels of proteins regulating hepatic lipids and liver fibrosis were similar in NASH and NASH-associated HCC. Systemic and hepatic Chemerin, and Chemerin receptor activation were not changed in HCC. Liver tumors only developed in diethylnitrosamine-injected mice and their number was increased in NASH. Chemerin protein was induced in liver in NASH, but was unchanged in HCC tissues. Conclusion Hepatic and serum Chemerin and ex vivo analyzed Chemerin receptor activation do not differ in murine NASH-associated HCC when compared to NASH. Hepatic tumors still develop despite high endogenous levels of serum and liver Chemerin protein.
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Chemerin neutralization blocks hematopoietic stem cell osteoclastogenesis
Stem cells (Dayton Ohio), 2013Co-Authors: Shanmugam Muruganandan, Jillian L Rourke, Helen J Dranse, Nichole Mcmullen, Christopher J. SinalAbstract:Bone is a dynamic tissue that is continuously remodeled through the action of formative osteoblasts and resorptive osteoclasts. Chemerin is a secreted protein that activates chemokine-like receptor 1 (CMKLR1), a G protein-coupled receptor expressed by various cell types including adipocytes, osteoblasts, mesenchymal stem cells (MSCs), and macrophages. Previously, we identified Chemerin as a regulator of adipocyte and osteoblast differentiation of MSCs. Herein we examined the role of Chemerin in Lin(-) Sca1(+) c-kit(+) CD34(+) hematopoietic stem cell (HSC) osteoclastogenesis. We found that HSCs expressed both Chemerin and CMKLR1 mRNA and secreted Chemerin protein into the extracellular media. Neutralization of Chemerin with a blocking antibody beginning prior to inducing osteoclast differentiation resulted in a near complete loss of osteoclastogenesis as evidenced by reduced marker gene expression and matrix resorption. This effect was conserved in an independent model of RAW264.7 cell osteoclastogenesis. Reintroduction of Chemerin by reversal of neutralization rescued osteoclast differentiation indicating that Chemerin signaling is essential to permit HSC differentiation into osteoclasts but following blockade the cells maintained the potential to differentiate into osteoclasts. Mechanistically, neutralization of Chemerin blunted the early receptor activator of nuclear factor-kappa B ligand induction of nuclear factor of activated T-cells 2 (NFAT2), Fos, Itgb3, and Src associated with preosteoclast formation. Consistent with a central role for NFAT2, induction or activation of NFAT2 by forced expression or stimulation of intracellular calcium release rescued the impairment of HSC osteoclastogenesis caused by Chemerin neutralization. Taken together, these data support a novel autocrine/paracrine role for Chemerin in regulating osteoclast differentiation of HSCs through modulating intracellular calcium and NFAT2 expression/activation.
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Chemerin connects fat to arterial contraction
Arteriosclerosis thrombosis and vascular biology, 2013Co-Authors: Stephanie W Watts, Christopher J. Sinal, Janice M. Thompson, Jillian L Rourke, Anne M. Dorrance, Mark E. Penfold, Bridget M Seitz, Timothy J. Sullivan, Trevor T. Charvat, Robert BurnettAbstract:Objective— Obesity and hypertension are comorbid in epidemic proportion, yet their biological connection is largely a mystery. The peptide Chemerin is a candidate for connecting fat deposits around the blood vessel (perivascular adipose tissue) to arterial contraction. We presently tested the hypothesis that Chemerin is expressed in perivascular adipose tissue and is vasoactive, supporting the existence of a Chemerin axis in the vasculature. Approach and Results— Real-time polymerase chain reaction, immunohistochemistry, and Western analyses supported the synthesis and expression of Chemerin in perivascular adipose tissue, whereas the primary Chemerin receptor ChemR23 was expressed both in the tunica media and endothelial layer. The ChemR23 agonist Chemerin-9 caused receptor, concentration-dependent contraction in the isolated rat thoracic aorta, superior mesenteric artery, and mesenteric resistance artery, and contraction was significantly amplified (more than 100%) when nitric oxide synthase was inhibited and the endothelial cell mechanically removed or tone was placed on the arteries. The novel ChemR23 antagonist CCX832 inhibited phenylephrine-induced and prostaglandin F2α-induced contraction (+perivascular adipose tissue), suggesting that endogenous Chemerin contributes to contraction. Arteries from animals with dysfunctional endothelium (obese or hypertensive) demonstrated a pronounced contraction to Chemerin-9. Finally, mesenteric arteries from obese humans demonstrate amplified contraction to Chemerin-9. Conclusions— These data support a new role for Chemerin as an endogenous vasoconstrictor that operates through a receptor typically attributed to function only in immune cells.
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towards an integrative approach to understanding the role of Chemerin in human health and disease
Obesity Reviews, 2013Co-Authors: Jillian L Rourke, Helen J Dranse, Christopher J. SinalAbstract:Abstract Chemerin is an adipocyte-secreted protein with autocrine/paracrine roles on adipose development and function as well as endocrine roles in metabolism and immunity. Following proChemerin secretion, protease-mediated generation of Chemerin isoforms with a range of biological activities is a key regulatory mechanism controlling local, context-specific Chemerin bioactivity. Together, experimental and clinical data indicate that localized and/or circulating Chemerin expression and activation are elevated in numerous metabolic and inflammatory diseases including psoriasis, obesity, type 2 diabetes, metabolic syndrome and cardiovascular disease. These elevations are positively correlated with deleterious changes in glucose, lipid, and cytokine homeostasis, and may serve as a link between obesity, inflammation and other metabolic disorders. This review highlights the current state of knowledge regarding Chemerin expression, processing, biological function and relevance to human disease, particularly with respect to adipose tissue development, inflammation, glucose homeostasis and cardiovascular disease. Furthermore, it discusses study variability, deficiencies in current measurement, and questions concerning Chemerin function in disease, with a special emphasis on techniques and tools used to properly assess Chemerin biology. An integration of basic and clinical research is key to understanding how Chemerin influences disease pathobiology, and whether modulation of Chemerin levels and/or activity may serve as a potential method to prevent and treat metabolic diseases.
Valerie Wittamer - One of the best experts on this subject based on the ideXlab platform.
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Expression of Bioactive Chemerin by Keratinocytes Inhibits Late Stages of Tumor Development in a Chemical Model of Skin Carcinogenesis
Frontiers in Oncology, 2019Co-Authors: Ingrid Dubois-vedrenne, Olivier De Henau, Virginie Robert, Francina Langa, Diana Al Delbany, Olivier Vosters, Edgar Angelats-canals, Maxime Vernimmen, Souphalone Luangsay, Valerie WittamerAbstract:Chemerin is a multifunctional protein acting mainly through the G protein-coupled receptor ChemR23/CMKLR1/Chemerin1. Its expression is frequently downregulated in human tumors, including in melanoma and squamous cell carcinoma of the skin and anti-tumoral properties of Chemerin were reported in mouse tumor graft models. In the present study, we report the development of spontaneous skin tumors in aged ChemR23-deficient mice. In order to test the potential therapeutic benefit of Chemerin analogs, a transgenic model in which bioactive Chemerin is over-expressed by basal keratinocytes was generated. These animals are characterized by increased levels of Chemerin immunoreactivity and bioactivity in the skin and the circulation. In a chemical carcinogenesis model, papillomas developed later, were less numerous, and their progression to carcinomas was delayed. Temporal control of Chemerin expression by doxycycline allowed to attribute its effects to late stages of carcinogenesis. The protective effects of Chemerin were partly abrogated by ChemR23 invalidation. These results demonstrate that Chemerin is able to delay very significantly tumor progression in a model that recapitulates closely the evolution of solid cancer types in human and suggest that the Chemerin-ChemR23 system might constitute an interesting target for therapeutic intervention in the cancer field.
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Chemerin and its receptors in leukocyte trafficking, inflammation and metabolism.
Cytokine & growth factor reviews, 2011Co-Authors: Benjamin Bondue, Valerie Wittamer, Marc ParmentierAbstract:Chemerin was isolated as the natural ligand of the G protein-coupled receptor ChemR23. Chemerin acts as a chemotactic factor for leukocyte populations expressing ChemR23, particularly immature plasmacytoid dendritic cells, but also immature myeloid DCs, macrophages and natural killer cells. Chemerin is expressed by epithelial and non-epithelial cells as an inactive precursor, present at nanomolar concentrations in plasma. Processing of the precursor C-terminus is required for generating bioactive forms of Chemerin. Various proteases mediate this processing, including neutrophil serine proteases and proteases from coagulation and fibrinolytic cascades. ChemR23-expressing cells are recruited in human inflammatory diseases, such as psoriasis and lupus. In animal models, both pro-inflammatory and anti-inflammatory roles of Chemerin have been reported. Recently, two other receptors for Chemerin were described, GPR1 and CCRL2, but their functional relevance is largely unknown. Both Chemerin and ChemR23 are also expressed by adipocytes, and the emerging role of Chemerin as an adipokine regulating lipid and carbohydrate metabolism is an area of intense research.
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role of neutrophil proteinase 3 and mast cell chymase in Chemerin proteolytic regulation
Journal of Leukocyte Biology, 2008Co-Authors: Aude Guillabert, Valerie Wittamer, Marc Parmentier, Virginie Imbault, Benjamin Bondue, Veronique Godot, David CommuniAbstract:Chemerin is a potent chemotactic factor that was identified recently as the ligand of ChemR23, a G protein-coupled receptor expressed by mononuclear phagocytes, dendritic cells (DCs), and NK cells. Chemerin is synthesized as a secreted precursor, proChemerin, which is poorly active on ChemR23. However, proChemerin can be converted rapidly into a full ChemR23 agonist by proteolytic removal of a carboxy-terminal peptide. This maturation step is mediated by the neutrophil-derived serine proteases elastase and cathepsin G. In the present work, we have investigated proteolytic events that negatively control Chemerin activity. We demonstrate here that neutrophil-derived proteinase 3 (PR3) and mast cell (MC) chymase are involved in the generation of specific Chemerin variants, which are inactive, as they do not induce calcium release or DC chemotaxis. Mass spectrometry analysis showed that PR3 specifically converts proChemerin into a Chemerin form, lacking the last eight carboxy-terminal amino acids, and is inactive on ChemR23. Whereas PR3 had no effect on bioactive Chemerin, MC chymase was shown to abolish Chemerin activity by the removal of additional amino acids from its C-terminus. This effect was shown to be specific to bioactive Chemerin (Chemerin-157 and to a lesser extent, Chemerin-156), as MC chymase does not use proChemerin as a substrate. These mechanisms, leading to the production of inactive variants of Chemerin, starting from the precursor or the active variants, highlight the complex interplay of proteases regulating the bioactivity of this novel mediator during early innate immune responses.
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Chemerin a new adipokine that modulates adipogenesis via its own receptor
Biochemical and Biophysical Research Communications, 2007Co-Authors: Sanggun Roh, Sanghoun Song, Kichoon Choi, Kazuo Katoh, Valerie Wittamer, Marc Parmentier, Shinichi SasakiAbstract:Chemerin, an 18 kDa protein secreted by adipose tissue, was reported to modulate immune system function through its binding to the Chemerin receptor (ChemerinR). We herein demonstrate that Chemerin also influences adipose cell function. Our data showed that Chemerin and ChemerinR mRNA expressions were highly expressed in adipose tissues, and that their expression levels were up-regulated in mice fed a high-fat diet. Both Chemerin and ChemerinR mRNA expression dramatically increased during the differentiation of 3T3-L1 cells and human preadipocytes into adipocytes. Furthermore, recombinant Chemerin induced the phosphorylation of extracellular signal-regulated kinases 1/2 (ERK 1/2) and lipolysis in differentiated 3T3-L1 adipocytes. Thus, the adipokine Chemerin likely regulates adipocyte function by autocrine/paracrine mechanisms.
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The C-terminal nonapeptide of mature Chemerin activates the Chemerin receptor with low nanomolar potency.
The Journal of biological chemistry, 2003Co-Authors: Valerie Wittamer, Françoise Grégoire, Patrick Robberecht, Gilbert Vassart, David Communi, Marc ParmentierAbstract:Chemerin is a novel protein identified as the natural ligand of ChemR23 (ChemerinR), a previously orphan G protein-coupled receptor expressed in immature dendritic cells and macrophages. Chemerin is synthesized as a secreted precursor, proChemerin, which is poorly active, but converted into a full agonist of ChemerinR by proteolytic removal of the last six amino acids. In the present work, we have synthesized a number of peptides derived from the C-terminal domain of human proChemerin and have investigated their functional properties as agonists or antagonists of human ChemerinR. We found that the nonapeptide (149)YFPGQFAFS(157) (Chemerin-9), corresponding to the C terminus of processed Chemerin, retained most of the activity of the full-size protein, with regard to agonism toward the ChemerinR. Extension of this peptide at its N terminus did not increase the activity, whereas further truncations rapidly resulted in inactive compounds. The C-terminal end of the peptide appeared crucial for its activity, as addition of a single amino acid or removal of two amino acids modified the potency by four orders of magnitude. Alanine-scanning mutagenesis identified residues Tyr(149), Phe(150), Gly(152), Phe(154), and Phe(156) as the key positions for ChemerinR activation. A modified peptide (YHSFFFPGQFAFS) was synthesized and iodinated, and a radioligand binding assay was established. It was found that the ability of the various peptides to activate the Chemerin receptor was strictly correlated with their affinity in the binding assay. These results confirm that a precise C-terminal processing is required for the generation of a ChemerinR agonist. The possibility to restrict a medium sized protein to a nonapeptide, while keeping a low nanomolar affinity for its receptor is unusual among G protein-coupled receptors ligands. The identification of these short bioactive peptides will considerably accelerate the pharmacological analysis of Chemerin-ChemerinR interactions.
Charalampos Aslanidis - One of the best experts on this subject based on the ideXlab platform.
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Chemerin Isoforms and Activity in Obesity
International journal of molecular sciences, 2019Co-Authors: Christa Buechler, Elisabeth M. Haberl, Susanne Feder, Charalampos AslanidisAbstract:Overweight and adiposity are risk factors for several diseases, like type 2 diabetes and cancer. White adipose tissue is a major source for adipokines, comprising a diverse group of proteins exerting various functions. Chemerin is one of these proteins whose systemic levels are increased in obesity. Chemerin is involved in different physiological and pathophysiological processes and it regulates adipogenesis, insulin sensitivity, and immune response, suggesting a vital role in metabolic health. The majority of serum Chemerin is biologically inert. Different proteases are involved in the C-terminal processing of Chemerin and generate diverse isoforms that vary in their activity. Distribution of Chemerin variants was analyzed in adipose tissues and plasma of lean and obese humans and mice. The Tango bioassay, which is suitable to monitor the activation of the beta-arrestin 2 pathway, was used to determine the ex-vivo activation of Chemerin receptors by systemic Chemerin. Further, the expression of the Chemerin receptors was analyzed in adipose tissue, liver, and skeletal muscle. Present investigations assume that increased systemic Chemerin in human obesity is not accompanied by higher biologic activity. More research is needed to fully understand the pathways that control Chemerin processing and Chemerin signaling.
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Hepatic Chemerin mRNA expression is reduced in human nonalcoholic steatohepatitis.
European journal of clinical investigation, 2016Co-Authors: Rebekka Pohl, Kristina Eisinger, Elisabeth M. Haberl, Lisa Rein-fischboeck, Sebastian Zimny, Maximilian Neumann, Charalampos Aslanidis, Doris Schacherer, Sabrina Krautbauer, Thomas S. WeissAbstract:Background Chemerin is associated with insulin resistance and is expressed in the liver. Nonalcoholic fatty liver disease (NAFLD) is related to impaired insulin sensitivity, but studies evaluating hepatic and serum Chemerin in NAFLD resulted in discordant data. Materials and methods Chemerin mRNA was determined in the liver tissue obtained from 33 controls and 76 NAFLD patients. Chemerin serum levels were measured in a different cohort of patients with ultrasound-diagnosed NAFLD and the respective controls. Hepatic stellate cells and hepatocytes were exposed to selected metabolites and nuclear receptor agonists to study the regulation of Chemerin. Effect of recombinant Chemerin on hepatocyte released proteins was analysed. Results Hepatic Chemerin expression was not related to BMI, gender, type 2 diabetes and hypertension. Chemerin mRNA did not correlate with steatosis and was negatively associated with inflammation, fibrosis and nonalcoholic steatohepatitis (NASH) score. Patients with NASH had lower Chemerin mRNA compared to those with borderline NASH and controls. Factors with a role in NASH mostly did not regulate Chemerin in the liver cells. Of note, liver X receptor agonist reduced Chemerin protein. Serum Chemerin was not changed in NAFLD. Levels positively correlated with age, waist-to-hip ratio, systolic blood pressure, serum FGF21 and lipocalin 2, and negatively with transferrin saturation. Chemerin induced FGF21 in supernatants of primary human hepatocytes. Hepcidin, a major regulator of iron homoeostasis and lipocalin 2, were not regulated by Chemerin. Conclusion Chemerin mRNA is reduced in the liver of NASH patients, and liver X receptor seems to have a role herein.
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sterol regulatory element binding protein 2 srebp2 activation after excess triglyceride storage induces Chemerin in hypertrophic adipocytes
Endocrinology, 2011Co-Authors: Sabrina Bauer, Andreas Schaffler, Johanna Weigert, Markus Neumeier, Josef Wanninger, C Dorn, Sandra Schmidhofer, C Hellerbrand, Nicole Zimara, Charalampos AslanidisAbstract:Chemerin is an adipokine whose systemic concentration and adipose tissue expression is increased in obesity. Chemerin is highly abundant in adipocytes, yet the molecular mechanisms mediating its further induction in obesity have not been clarified. Adipocyte hypertrophy contributes to dysregulated adipokine synthesis, and we hypothesized that excess loading with free fatty acids (FFA) stimulates Chemerin synthesis. Chemerin was expressed in mature adipocytes, and differentiation of 3T3-L1 cells in the presence of FFA further increased its level. TNF and IL-6 were induced by FFA, but concentrations were too low to up-regulate Chemerin. Sterol regulatory element-binding protein 2 (SREBP2) was activated in these cells, indicative for cholesterol shortage. Suppression of cholesterol synthesis by lovastatin led to activation of SREBP2 and increased Chemerin, and supplementation with mevalonate reversed this effect. Knockdown of SREBP2 reduced basal and FFA-induced Chemerin. EMSA confirmed binding of 3T3-L1 adipocyte nuclear proteins to a SREBP site in the Chemerin promotor. SREBP2 was activated and Chemerin was induced in adipose tissue of mice fed a high-fat diet, and higher systemic levels seem to be derived from adipocytes. Lipopolysaccharide-mediated elevation of Chemerin was similarly effective as induction by FFA, indicating that both mechanisms are equally important. Chemokine-like receptor 1 was not altered by the incubations mentioned above, and higher expression in fat of mice fed a high-fat diet may reflect increased number of adipose tissue-resident macrophages in obesity. In conclusion, the current data show that adipocyte hypertrophy and chronic inflammation are equally important in inducing Chemerin synthesis.
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systemic Chemerin is related to inflammation rather than obesity in type 2 diabetes
Clinical Endocrinology, 2010Co-Authors: Johanna Weigert, Sabrina Bauer, Andreas Schaffler, Reiner Wiest, Markus Neumeier, Josef Wanninger, Michael Filarsky, S Farkas, Marcus N Scherer, Charalampos AslanidisAbstract:Background The adipokine Chemerin modulates the function of innate immune cells and may link obesity and inflammation, and therefore, a possible relation of Chemerin to inflammatory proteins in obesity and type 2 diabetes (T2D) was analysed. As visceral fat contributes to systemic inflammation, Chemerin was measured in portal venous (PVS), hepatic venous (HVS) and systemic venous (SVS) blood of patients with liver cirrhosis. Patients and methods Systemic Chemerin was determined by ELISA in the serum of normal-weight, overweight and T2D males, in the serum of T2D patients of both sexes, and in PVS, HVS and SVS of patients with liver cirrhosis. Results Circulating Chemerin was similar in T2D and obese individuals but was significantly elevated in both cohorts compared to normal-weight individuals. Chemerin positively correlated with leptin, resistin and C-reactive protein (CRP). In T2D, Chemerin was similar in male and female patients and increased in patients with elevated CRP. Chemerin was similar in PVS and SVS, indicating that visceral fat is not a major site of Chemerin synthesis. Higher levels of Chemerin in HVS demonstrate that Chemerin is also released by the liver. Conclusions Visceral fat is not a major site of Chemerin release, and elevated systemic levels of Chemerin in obesity and T2D seem to be associated with inflammation rather than body mass index.
Ping Feng - One of the best experts on this subject based on the ideXlab platform.
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elevated serum Chemerin concentrations are associated with renal dysfunction in type 2 diabetic patients
Diabetes Research and Clinical Practice, 2011Co-Authors: Ping FengAbstract:Abstract Aim Chemerin, a new adipocytokine, has been suggested to be linked to obesity-induced insulin resistance and type 2 diabetes. The association of plasma Chemerin levels with diabetic nephropathy, however, is unknown. Therefore, this study aims to determine whether plasma Chemerin levels are associated with renal function in type 2 diabetic patients. Methods A total of 116 type 2 diabetic patients and 38 healthy subjects were enrolled in this study. Serum levels of Chemerin were measured by enzyme-linked immunosorbent assay. Results Serum Chemerin was significantly elevated in type 2 diabetic patients with macroalbuminuria compared with control subjects and diabetic patients with normoalbuminuria and microalbuminuria. No differences were found in the level of serum Chemerin between diabetic patients with normoalbuminuria and microalbuminuria and control subjects. Serum Chemerin was positively correlated with age, body mass index (BMI), systolic blood pressure (SBP), C-reactive protein (CRP), blood urea nitrogen (BUN), serum creatinine and serum triglycerides, and negatively correlated with creatinine clearance Stepwise regression analysis showed that creatinine clearance and serum creatinine remained significantly associated with serum Chemerin. Conclusion Serum Chemerin levels are strongly associated with renal function in diabetic patients.