Overexpression of juxtaposed with another zinc finger gene 1 reduces proinflammatory cytokine release via inhibition of stress‐activated protein kinases and nuclear factor‐κB

Abstract

As an inhibitor of the nuclear receptor subfamily 2, group C, member 2 signaling pathway, juxtaposed with another zinc finger gene 1 (JAZF1) has been shown to be involved in gluconeogenesis, lipid metabolism, and insulin sensitivity. However, its role in hepatic lipogenesis and chronic lowgrade inflammation leading to nonalcoholic fatty liver disease remains unknown. The aim of this study was to examine whether JAZF1 overexpression in vivo or in vitro can protect against palmitic acid (PA)-induced and high-fat diet (HFD)-induced systemic inflammatory responses, and the potential mechanism of this process. JAZF1 overexpression vector was transfected into PA-treated IAR-20 hepatocytes. The mRNA expression levels of proinflammatory cytokines were measured by real-time quantitative PCR, and stress-activated protein kinase activities were measured by immunoblotting. For in vivo studies, JAZF1 transgenic mice were fed an HFD for 12 weeks. Liver tissue was obtained for histological examination, real-time RT-PCR, and western blot analysis. PA significantly increased the expression levels of tumor necrosis factor-a, monocyte chemotactic protein-1 and interleukin-8 mRNA in IAR-20 hepatocytes in a dose-dependent and time-dependent manner. Treatment with JAZF1 or stress-activated protein kinase inhibitors inhibited PA-induced tumor necrosis factor-a, monocyte chemotactic protein-1 and interleukin-8 expression in these cells. In JAZF1-treated cells, the decreased expression of proinflammatory cytokines was accompanied by decreased p38 mitogen-activated protein kinase and c-Jun N-terminal kinase phosphorylation and increased nuclear factorjB inhibitor-a protein levels, similarly to the role of signaling inhibitors. In vivo, HFD-induced expression of proinflammatory cytokines was markedly attenuated in JAZF1-Tg mice as compared with controls. This attenuation was accompanied by decreased activation of c-Jun N-terminal kinase, p38 mitogen-activated protein kinase, and nuclear factor-jB. These data provide evidence for the important role of JAZF1 in preventing lipogenesis and systemic inflammation-related disease.

KPNβ1 promotes palmitate-induced insulin resistance via NF-κB signaling in hepatocytes

“…Through lipid infusion, the increased plasma FFA can cause insulin resistance in mice and human hepatocytes. FFAinduced impairment of insulin sensitivity in hepatocytes is displayed as decreased phosphorylation levels of IRS1 and AKT [9,34]. In this study, we treated hepatocytes with PA to mimic the increased FFA infusion into cells.…”

Role of bone morphogenetic protein‐9 in the regulation of glucose and lipid metabolism

“…Signaling Technology), anti-b-actin (17AV0410; ZSGB-BIO, Beijing, China); and secondary antibody, as previously described (24). The results of RT-PCR and Western blot were normalized to housekeeping gene b-actin.…”

JAZF1, a relevant metabolic regulator in type 2 diabetes

“…The effect of nutritional status on JAZF1 expression is also demonstrated in in vitro cell studies. Studies show that high concentration of palmitic acid (PA) and glucose, respectively, suppresses JAZF1 expression in hepatocytes and islet cells . The above‐mentioned results reveal that diet, especially the metabolic disturbance, is an important modulator in JAZF1 expression.…”