Sterol Regulatory Element-Binding Protein 2 (SREBP2) Activation after Excess Triglyceride Storage Induces Chemerin in Hypertrophic Adipocytes

Abstract

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.

ChemR23 knockout mice display mild obesity but no deficit in adipocyte differentiation

“…On being fed a HFD, no difference in body weight and cholesterol levels were observed between ChemR23 KO and control mice, indicating that the chemerin/ChemR23 system has more effect under normocaloric conditions. HFD promoted the upregulation of chemerin expression in WAT, in accordance with the findings reported by Bauer et al (2011), and ChemR23 expression was also upregulated. The upregulation of chemerin expression in adipose tissue was not associated with higher chemerin levels in blood, suggesting that WAT might not represent the main source of circulating chemerin, even in mice with increased adipose tissue mass.…”

La chémérine

“…La restauration de l'homéostasie du cholestérol y induit la synthèse de chémérine. Ainsi, un faible taux de cholestérol est directement lié à une augmentation de l'expression de la chémérine [34]. Chez la vache, Muruganandan et son équipe ont montré que le gène codant la chémérine possède aussi, dans sa région promotrice, des éléments de réponse à PPAR- (peroxisome proliferator response element -PPRE), ce qui est en accord avec les données de Suzuki et al qui ont observé une augmentation simultanée de l'expression de PPAR-2 et de la chémérine au cours de la différenciation des adipocytes bovins [31,35].…”

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

“…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 liver chemerin mRNA positively correlates with NAFLD activity score, and is induced in patients with NASH [9,28].…”

“…In adipocytes chemerin is induced by proinflammatory cytokines, Lipopolysaccharide (LPS), Free Fatty Acids (FFA) and insulin [12,[14][15][16][17], which are all increased in obesity [18][19][20], and this may contribute to elevated systemic chemerin. Three studies recently published investigated whether these metabolites also regulate hepatocyte chemerin synthesis [9,10,21].…”

“…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].…”