title: 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 low-grade 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-α, 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-α, 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 factor-κB inhibitor-α 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-κB. These data provide evidence for the important role of JAZF1 in preventing lipogenesis and systemic inflammation-related disease.
authors.affiliation: Department of Endocrinology, the Second Affiliated Hospital, Chongqing Medical University, China.
authors.forename: Mengliu
authors.initials: M
authors.lastname: Yang
authors.forename: Jihuan
authors.initials: J
authors.lastname: Dai
authors.forename: Yanjun
authors.initials: Y
authors.lastname: Jia
authors.forename: Langquzhen
authors.initials: L
authors.lastname: Suo
authors.forename: Shengbing
authors.initials: S
authors.lastname: Li
authors.forename: Yunsong
authors.initials: Y
authors.lastname: Guo
authors.forename: Hua
authors.initials: H
authors.lastname: Liu
authors.forename: Ling
authors.initials: L
authors.lastname: Li
authors.forename: Gangyi
authors.initials: G
authors.lastname: Yang
mesh_terms: D000818:Animals; D018932:Chemokine CCL2 / Q000096:biosynthesis; D056970:Co-Repressor Proteins; D016207:Cytokines / Q000096:biosynthesis; D004268:DNA-Binding Proteins; D059305:Diet, High-Fat; D005234:Fatty Liver / Q000188:drug therapy; D016209:Interleukin-8 / Q000096:biosynthesis; D047908:Intracellular Signaling Peptides and Proteins; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009363:Neoplasm Proteins / Q000096:biosynthesis / Q000502:physiology*; D065626:Non-alcoholic Fatty Liver Disease; D019308:Palmitic Acid / Q000494:pharmacology; D011506:Proteins / Q000378:metabolism; D015398:Signal Transduction; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis*
chemical_list: D018932:Chemokine CCL2; D056970:Co-Repressor Proteins; D016207:Cytokines; D004268:DNA-Binding Proteins; D016209:Interleukin-8; D047908:Intracellular Signaling Peptides and Proteins; D009363:Neoplasm Proteins; D019308:Palmitic Acid; D011506:Proteins; D014409:Tumor Necrosis Factor-alpha; C491768:Ccl2 protein, mouse; C454819:Nfkbid protein, mouse; C430460:JAZF1 protein, human
keywords: hepatic steatosis; juxtaposed with another zinc finger gene 1 (JAZF1); proinflammatory cytokine; systemic inflammatory responses