Hepatocyte expressed chemerin-156 does not protect from experimental non-alcoholic steatohepatitis

Abstract

Non-alcoholic steatohepatitis (NASH) is a rapidly growing liver disease. The chemoattractant chemerin is abundant in hepatocytes, and hepatocyte expressed prochemerin protected from NASH. Prochemerin is inactive and different active isoforms have been described. Here, the effect of hepatocyte expressed muChem-156, a highly active murine chemerin isoform, was studied in the methionine–choline deficient dietary model of NASH. Mice overexpressing muChem-156 had higher hepatic chemerin protein. Serum chemerin levels and the capability of serum to activate the chemerin receptors was unchanged showing that the liver did not release active chemerin. Notably, activation of the chemerin receptors by hepatic vein blood did not increase in parallel to total chemerin protein in patients with liver cirrhosis. In experimental NASH, muChem-156 had no effect on liver lipids. Accordingly, overexpression of active chemerin in hepatocytes or treatment of hepatocytes with recombinant chemerin did not affect cellular triglyceride and cholesterol levels. Importantly, overexpression of muChem-156 in the murine liver did not change the hepatic expression of inflammatory and profibrotic genes. The downstream targets of chemerin such as p38 kinase were neither activated in the liver of muChem-156 producing mice nor in HepG2, Huh7 and Hepa1-6 cells overexpressing this isoform. Recombinant chemerin had no effect on global gene expression of primary human hepatocytes and hepatic stellate cells within 24 h of incubation. Phosphorylation of p38 kinase was, however, increased upon short-time incubation of HepG2 cells with chemerin. These findings show that muChem-156 overexpression in hepatocytes does not protect from liver steatosis and inflammation.

Anti-Tumoral Effect of Chemerin on Ovarian Cancer Cell Lines Mediated by Activation of Interferon Alpha Response

“…We first examined the effect of bioactive recombinant human chemerin (huChem-157) (R&D Systems, 2324-CM-025) on ovarian cancer cell lines in standard adherent 2D culture conditions. To choose the concentrations for treatment, we considered a study reporting that 100 ng/mL of huChem-157 is equivalent to a concentration of 25 ng/mL chemerin using standard ELISA [ 44 ]. Thus, we used 100 and 400 ng/mL of huChem-157, being equivalent to 25 or 100 ng/mL serum chemerin, which represents the usual range from non-obese to obese patients in vivo [ 45 ].…”

“…All observed in vitro effects of chemerin were triggered only by the higher concentration of 400 ng/mL of recombinant huChem-157, which is equivalent to 100 ng/mL chemerin in human serum. Initially, concentrations of 100 and 400 ng/mL were chosen for our experiments considering a study reporting that 100 ng/mL of recombinant huChem-157 is equivalent to a concentration of 25 ng/mL chemerin using standard ELISA, thus being comparable to usual chemerin serum levels between 25 and 100 ng/mL [ 44 ]. However, a weakness of this study is that we did not compare the effect of 100 and 400 ng/mL Chem-157 in each experiment, because in the initial experiment we observed that only the higher concentration showed an effect in 2D cell culture.…”