Identification of Chemerin as a Novel FXR Target Gene Down-Regulated in the Progression of Nonalcoholic Steatohepatitis

Abstract

Chemerin is an adipokine involved in obesity, inflammation, and innate immune system that is highly expressed in the liver. In the present study, we find that chemerin mRNA expression is decreased in the livers of rodents with nonalcoholic fatty liver disease as well as in HepG2 cells after lipid overloading. Moreover, we report that chemerin expression and secretion are induced in HepG2 cells and primary hepatocytes from wild-type mice, but not farnesoid X receptor (FXR)-/- mice, in response to the synthetic FXR ligand GW4064. Hepatic chemerin expression is decreased in FXR-/- mice but up-regulated by GW4064 administration in wild-type mice. Dual-luciferase reporter assay and chromatin immunoprecipitation analyses further identified a functional FXR response element located in the -258-bp /+121-bp region of the chemerin gene. These data demonstrate that chemerin, a novel target gene of FXR, is related to nonalcoholic steatohepatitis.

Chemerin in Non-Alcoholic Fatty Liver Disease ? Up or Down?

“…While one study has found increased hepatic chemerin protein, a second study describes reduced mRNA levels in this animal model. Serum chemerin is shown to be lower in MCD fed animals in accordance with reduced body weight while systemic chemerin is also found to be similar compared with chow fed animals [10,21]. Mice fed an atherogenic diet known to cause hepatic steatosis, inflammation and fibrosis have a trend to higher hepatic chemerin protein while serum chemerin is increased most likely because of higher body weight [10,14].…”

“…In humans hepatic chemerin mRNA expression positively correlates with BMI, and steatosis grade [9] and mRNA levels tend to be higher in patients with liver steatosis compared to controls [9,10]. Anyway, decreased hepatic chemerin mRNA in db/db mice, animals fed a high fat diet for two months and human fatty liver has also been described [21].…”

“…Farnesoid X receptor is reduced in NAFLD [23], and its agonist GW4064 increases chemerin in HepG2 cells and in the liver of mice [21]. Food restriction and refeeding do not affect hepatic chemerin mRNA while adipose tissue expression is reduced upon prolonged fasting and increased by refeeding [24].…”

“…Palmitate even strongly reduces chemerin mRNA and protein in the supernatants of HepG2 cells [21]. Thus, in contrast to adipocytes, increased lipid storage in hepatocytes, which is used as an in-vitro model for liver steatosis, does not induce chemerin in primary hepatocytes and may even reduce its level in hepatoma cells [9,10,14,21].…”

“…Three studies recently published investigated whether these metabolites also regulate hepatocyte chemerin synthesis [9,10,21]. IL-6 has, however, no effect on chemerin mRNA, cellular and soluble protein, and LPS does not increase chemerin protein in Primary Human Hepatocytes (PHH) [9,10].…”