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.

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.