title: Overexpression of JAZF1 protected ApoE-deficient mice from atherosclerosis by inhibiting hepatic cholesterol synthesis via CREB-dependent mechanisms.
abstract: Genome wide association studies have suggested an association of Juxtaposed with another zinc finger gene 1(JAZF1) with type 2 diabetes mellitus (T2DM). As an inhibitor of the TAK1/TR4 signaling pathway, JAZF1 has been shown to be involved in gluconeogenesis, lipid metabolism and insulin sensitivity. However, its role in insulin resistance and atherosclerosis in vivo remains unknown. The present study was designed to investigate in vivo the impact of JAZF1 on insulin resistance-associated dyslipidemia and atherosclerosis. Adenovirus-mediated JAZF1 overexpression was used to characterize the role of JAZF1 in the regulation of lipid metabolism and the development of atherosclerosis in normal chow- or HFD-fed ApoE KO mice. Insulin sensitivity was examined by EHC. Cholesterol de novo synthesis was measured by intraperitoneal [1-(14)C] acetate injection and atherosclerotic plaques were quantified by histological analysis. A dual-luciferase reporter assay was used to assess the ability of JAZF1 to regulate HMGCR transcriptional activity. JAZF1 overexpression improved HFD-induced hepatic insulin resistance in C57BL/6J mice. In HFD-fed ApoE KO mice, JAZF1 overexpression decreased serum cholesterol levels and hepatic cholesterol synthesis by inhibiting CREB-dependent HMGCR promoter transcriptional activity. Analysis of atherosclerotic lesion showed that JAZF1 overexpression had significantly reduced aortic and aortic sinus en face and cross-sectional plaque areas in HFD-fed ApoE KO mice. These data provide the first evidence for an important role of JAZF1 in increasing hepatic insulin sensitivity and preventing atherosclerosis.
authors.affiliation: The Key Laboratory of Laboratory Medical Diagnostics in the Ministry of Education and Department of Clinical Biochemistry, College of Laboratory Medicine, Chongqing Medical University, 400016 Chongqing, China.
authors.forename: Xiaoqiang
authors.initials: X
authors.lastname: Li
authors.affiliation: The Key Laboratory of Laboratory Medical Diagnostics in the Ministry of Education and Department of Clinical Biochemistry, College of Laboratory Medicine, Chongqing Medical University, 400016 Chongqing, China.
authors.forename: Mengliu
authors.initials: M
authors.lastname: Yang
authors.affiliation: The Key Laboratory of Laboratory Medical Diagnostics in the Ministry of Education and Department of Clinical Biochemistry, College of Laboratory Medicine, Chongqing Medical University, 400016 Chongqing, China.
authors.forename: Han
authors.initials: H
authors.lastname: Wang
authors.affiliation: Department of Endocrinology, the Second Affiliated Hospital, Chongqing Medical University, 400010 Chongqing, China.
authors.forename: Yanjun
authors.initials: Y
authors.lastname: Jia
authors.affiliation: Department of Endocrinology, the Second Affiliated Hospital, Chongqing Medical University, 400010 Chongqing, China.
authors.forename: Pijun
authors.initials: P
authors.lastname: Yan
authors.affiliation: The Division of Endocrinology/Diabetes/Metabolism and the Clinical Research Center, Temple University School of Medicine, Philadelphia, PA, USA.
authors.forename: Guenther
authors.initials: G
authors.lastname: Boden
authors.affiliation: The Key Laboratory of Laboratory Medical Diagnostics in the Ministry of Education and Department of Clinical Biochemistry, College of Laboratory Medicine, Chongqing Medical University, 400016 Chongqing, China. Electronic address: gangyiyang@163.com.
authors.forename: Gangyi
authors.initials: G
authors.lastname: Yang
authors.affiliation: The Key Laboratory of Laboratory Medical Diagnostics in the Ministry of Education and Department of Clinical Biochemistry, College of Laboratory Medicine, Chongqing Medical University, 400016 Chongqing, China. Electronic address: liling31@hotmail.com.
authors.forename: Ling
authors.initials: L
authors.lastname: Li
mesh_terms: D000818:Animals; D001057:Apolipoproteins E / Q000172:deficiency; D050197:Atherosclerosis / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D002352:Carrier Proteins / Q000096:biosynthesis / Q000235:genetics*; D002478:Cells, Cultured; D002784:Cholesterol / Q000096:biosynthesis*; D056970:Co-Repressor Proteins; D004268:DNA-Binding Proteins; D004195:Disease Models, Animal; D005786:Gene Expression Regulation; D007333:Insulin Resistance; D008099:Liver / Q000378:metabolism* / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009687:Nuclear Proteins / Q000096:biosynthesis / Q000235:genetics*; D012313:RNA / Q000235:genetics*; D060888:Real-Time Polymerase Chain Reaction; D015398:Signal Transduction
chemical_list: D001057:Apolipoproteins E; D002352:Carrier Proteins; D056970:Co-Repressor Proteins; D004268:DNA-Binding Proteins; C558308:JAZF1 protein, mouse; D009687:Nuclear Proteins; D012313:RNA; D002784:Cholesterol
keywords: Atherosclerosis; Cholesterol synthesis; Insulin resistance; JAZF1