Chemerin Isoforms and Activity in Obesity

Buechler, Christa; Feder, Susanne; Haberl, Elisabeth M.; Aslanidis, Charalampos

doi:10.3390/ijms20051128

Cited by 127 publications

(172 citation statements)

References 86 publications

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“…Chemerin is expressed at the highest levels in the liver and white adipose tissue (1), organs that contribute to fatty acid metabolism, respond to numerous cytokines, and are involved in the pathophysiology of obesity (25). Many studies confirmed a relationship between serum chemerin and fat mass in overweight/obese individuals and correlations with obesity-associated traits, like low-grade inflammation, hypertension, and insulin resistance in some but not all of the patient cohorts studied (36). Both cytokines, IL-1β and OSM, are linked with low-grade inflammation in obesity.…”

Section: Discussionmentioning

confidence: 99%

Novel insights into the regulation of chemerin expression: role of acute-phase cytokines and DNA methylation

Kwiecień

Brzoza

Majewski

et al. 2019

Preprint

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Chemerin is a chemoattractant protein with adipokine properties encoded by the retinoic acid receptor responder 2 (RARRES2) gene. It has gained more attention over the past few years due to its multilevel impact on metabolism and immune responses. The pleiotropic actions of chemerin include chemotaxis of dendritic cells, macrophages and natural killers (NK) subsets, bactericidal activity as well as regulation of adipogenesis and glucose metabolism. Therefore, reflecting the pleiotropic actions of chemerin, expression of RARRES2 is regulated by a variety of inflammatory and metabolic mediators.However, for most cell types, the molecular mechanisms controlling constitutive and regulated chemerin expression are poorly characterized. Here we show that RARRES2 mRNA levels in murine adipocytes are upregulated in vitro and in vivo by acute-phase cytokines, IL-1 and OSM. In contrast to adipocytes, these cytokines exerted a weak, if any, response in mouse hepatocytes, suggesting that the effect of IL-1 and OSM on chemerin expression is specific to fat tissue. Moreover, we show that DNA methylation controls the constitutive expression of chemerin. Bisulfite sequencing analysis showed low methylation levels within -735 to +258 bp of the murine RARRES2 gene promoter in unstimulated adipocytes and hepatocytes. In contrast to these cells, the RARRES2 promoter is highly methylated in B lymphocytes, cells that do not produce chemerin. Together, our findings reveal previously uncharacterized mediators and mechanisms controlling chemerin expression in various cells.

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Section: Discussionmentioning

confidence: 99%

Novel insights into the regulation of chemerin expression: role of acute-phase cytokines and DNA methylation

Kwiecień

Brzoza

Majewski

et al. 2019

Preprint

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“…The multifunctional chemokine chemerin acts through the G protein-coupled receptors chemokine-like receptor 1 (CMKLR1) and G protein-coupled receptor 1 (GPR1). Chemerin’s role as an attractant for immune cells is very well described [ 1 , 2 , 3 ]. More recent studies have identified potential roles for chemerin in different cancers [ 4 , 5 ].…”

Section: Introductionmentioning

confidence: 99%

“…This variant is referred to as chemerin 163 in the literature although the 20 N-terminal amino acids were removed. Prochemerin (huChem-163) can be activated by C-terminal proteolytic processing [ 1 , 10 , 11 ]. The human variants huChem-156, 157 and 158 are biologically active isoforms, while those with 155 or less amino acids are generally regarded as inactive [ 1 ].…”

Section: Introductionmentioning

confidence: 99%

Chemerin Isoform-Specific Effects on Hepatocyte Migration and Immune Cell Inflammation

Feder

Bruckmann

McMullen

et al. 2020

IJMS

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Murine chemerin is C-terminally processed to the bioactive isoforms, muChem-156 and muChem-155, among which the longer variant protects from hepatocellular carcinoma (HCC). However, the role of muChem-155 is mostly unknown. Here, we aimed to compare the effects of these isoforms on the proliferation, migration and the secretome of the human hepatocyte cell lines HepG2 and Huh7 and the murine Hepa1-6 cell line. Therefore, huChem-157 and -156 were overexpressed in the human cells, and the respective murine variants, muChem-156 and -155, in the murine hepatocytes. Both chemerin isoforms produced by HepG2 and Hepa1-6 cells activated the chemerin receptors chemokine-like receptor 1 (CMKLR1) and G protein-coupled receptor 1 (GPR1). HuChem-157 was the active isoform in the Huh7 cell culture medium. The potencies of muChem-155 and muChem-156 to activate human GPR1 and mouse CMKLR1 were equivalent. Human CMKLR1 was most responsive to muChem-156. Chemerin variants showed no effect on cell viability and proliferation. Activation of the mitogen-activated protein kinases Erk1/2 and p38, and protein levels of the epithelial–mesenchymal transition marker, E-cadherin, were not regulated by the chemerin variants. Migration was reduced in HepG2 and Hepa1-6 cells by the longer isoform. Protective effects of chemerin in HCC include the modulation of cytokines but huChem-156 and huChem-157 overexpression did not change IL-8, CCL20 or osteopontin in the hepatocytes. The conditioned medium of the transfected hepatocytes failed to alter these soluble factors in the cell culture medium of peripheral blood mononuclear cells (PBMCs). Interestingly, the cell culture medium of Huh7 cells producing the inactive variant huChem-155 reduced CCL2 and IL-8 in PBMCs. To sum up, huChem-157 and muChem-156 inhibited hepatocyte migration and may protect from HCC metastasis. HuChem-155 was the only human isoform exerting anti-inflammatory effects on immune cells.

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“…Chemerin is produced primarily by adipocytes and hepatocytes, and is secreted in a pro-form that is subsequently activated by C-terminal proteolysis [4,5]. Several chemerin isoforms are generated by this processing, with murine chemerin-156 and human chemerin-157 having the greatest chemoattractant activity for macrophages expressing the chemerin receptor chemokine-like receptor 1 (CMKLR1) [6].…”

Section: Introductionmentioning

confidence: 99%

Overexpression of Hepatocyte Chemerin-156 Lowers Tumor Burden in a Murine Model of Diethylnitrosamine-Induced Hepatocellular Carcinoma

Haberl

Pohl

Rein-Fischboeck

et al. 2019

IJMS

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The tumor inhibitory potential of the highly active chemerin-156 isoform was described in orthotopic models of hepatocellular carcinoma (HCC). The majority of HCC arises in the fibrotic liver, which was not reproduced in these studies. Here, a potential therapeutic activity of chemerin-156 was evaluated in diethylnitrosamine (DEN)-induced liver cancer, which mimics fibrosis-associated HCC. Mice were infected with adeno-associated virus (AAV) six months after DEN injection to overexpress chemerin-156 in the liver, and animals injected with non-recombinant-AAV served as controls. Three months later, the animals were killed. Both groups were comparable with regard to liver steatosis and fibrosis. Of note, the number of very small tumors was reduced by chemerin-156. Anyhow, the expression of inflammatory and profibrotic genes was similar in larger tumors of control and chemerin-156-AAV-infected animals. Although genes with a role in lipid metabolism, like 3-hydroxy-3-methylglutaryl-coenzym-A--reductase, were overexpressed in tumors of animals with high chemerin-156, total hepatic cholesterol, diacylglycerol and triglyceride levels, and distribution of individual lipid species were normal. Chemerin-156-AAV-infected mice had elevated hepatic and systemic chemerin. Ex vivo activation of the chemerin receptor chemokine-like receptor 1 increased in parallel with serum chemerin, illustrating the biological activity of the recombinant protein. In the tumors, chemerin-155 was the most abundant variant. Chemerin-156 was not detected in tumors of the controls and was hardly found in chemerin-156-AAV infected animals. In conclusion, the present study showed that chemerin-156 overexpression caused a decline in the number of small lesions but did not prevent the growth of pre-existing neoplasms.

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Chemerin Isoforms and Activity in Obesity

Cited by 127 publications

References 86 publications

Novel insights into the regulation of chemerin expression: role of acute-phase cytokines and DNA methylation

Novel insights into the regulation of chemerin expression: role of acute-phase cytokines and DNA methylation

Chemerin Isoform-Specific Effects on Hepatocyte Migration and Immune Cell Inflammation

Overexpression of Hepatocyte Chemerin-156 Lowers Tumor Burden in a Murine Model of Diethylnitrosamine-Induced Hepatocellular Carcinoma

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