title: Ajuba Preferentially Binds LXRα/RXRγ Heterodimer to Enhance LXR Target Gene Expression in Liver Cells.
abstract: The liver X receptors (LXRs) are important regulators of lipid, cholesterol, and glucose homeostasis by transcriptional regulation of many key genes in these processes, and the transcriptional activities of LXRs are finely controlled by cooperating with retinoid X receptors and many other coregulators. Here, we report that the LIM protein Ajuba binds to the hinge and the ligand binding domains of LXRα via its C-terminal tandem LIM motifs and enhances LXR target gene expression in liver cells. Depletion of Ajuba in HepG2 cells and in mouse primary hepatocytes decreases LXR target gene expression, whereas stable expression of Ajuba in HepG2 cells results in increased expression of these genes. Mechanistic investigations found that Ajuba selectively interacts with LXRα/retinoid X receptor-γ heterodimer to form a ternary complex, which displays a higher transactivation activity to LXR target genes. Moreover, Ajuba and LXR mutually affect their DNA binding activity at endogenous target chromatins and the cooperation between Ajuba and LXRα is dependent on the functional LXR response elements located in the target promoters. Together, our studies demonstrate that Ajuba is a novel coactivator for LXRs and may play important role in lipid and glucose metabolism.
authors.affiliation: Department of Endocrinology (H.F., S.L., W.L., Y.D.), Renji Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai, 200025 China; Hongqiao Institute of Medicine (H.F., Q.L., X.Z., Y.Z., J.W., Z.H.), Shanghai Tongren Hospital and Faculty of Basic Medicine, Shanghai Jiaotong University School of Medicine, Shanghai, 200025 China; Department of Pathophysiology (W.D., H.S.), Key Laboratory of Cell Differentiation and Apoptosis of Chinese Ministry of Education, Shanghai Jiaotong University School of Medicine, Shanghai, 200025 China; and Shanghai Key Laboratory for Tumor Microenvironment and Inflammation (Z.H.), Shanghai Jiaotong University School of Medicine, Shanghai, 200025 China.
authors.forename: Hongyan
authors.initials: H
authors.lastname: Fan
authors.affiliation: Department of Endocrinology (H.F., S.L., W.L., Y.D.), Renji Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai, 200025 China; Hongqiao Institute of Medicine (H.F., Q.L., X.Z., Y.Z., J.W., Z.H.), Shanghai Tongren Hospital and Faculty of Basic Medicine, Shanghai Jiaotong University School of Medicine, Shanghai, 200025 China; Department of Pathophysiology (W.D., H.S.), Key Laboratory of Cell Differentiation and Apoptosis of Chinese Ministry of Education, Shanghai Jiaotong University School of Medicine, Shanghai, 200025 China; and Shanghai Key Laboratory for Tumor Microenvironment and Inflammation (Z.H.), Shanghai Jiaotong University School of Medicine, Shanghai, 200025 China.
authors.forename: Weibing
authors.initials: W
authors.lastname: Dong
authors.affiliation: Department of Endocrinology (H.F., S.L., W.L., Y.D.), Renji Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai, 200025 China; Hongqiao Institute of Medicine (H.F., Q.L., X.Z., Y.Z., J.W., Z.H.), Shanghai Tongren Hospital and Faculty of Basic Medicine, Shanghai Jiaotong University School of Medicine, Shanghai, 200025 China; Department of Pathophysiology (W.D., H.S.), Key Laboratory of Cell Differentiation and Apoptosis of Chinese Ministry of Education, Shanghai Jiaotong University School of Medicine, Shanghai, 200025 China; and Shanghai Key Laboratory for Tumor Microenvironment and Inflammation (Z.H.), Shanghai Jiaotong University School of Medicine, Shanghai, 200025 China.
authors.forename: Qi
authors.initials: Q
authors.lastname: Li
authors.affiliation: Department of Endocrinology (H.F., S.L., W.L., Y.D.), Renji Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai, 200025 China; Hongqiao Institute of Medicine (H.F., Q.L., X.Z., Y.Z., J.W., Z.H.), Shanghai Tongren Hospital and Faculty of Basic Medicine, Shanghai Jiaotong University School of Medicine, Shanghai, 200025 China; Department of Pathophysiology (W.D., H.S.), Key Laboratory of Cell Differentiation and Apoptosis of Chinese Ministry of Education, Shanghai Jiaotong University School of Medicine, Shanghai, 200025 China; and Shanghai Key Laboratory for Tumor Microenvironment and Inflammation (Z.H.), Shanghai Jiaotong University School of Medicine, Shanghai, 200025 China.
authors.forename: Xiuqun
authors.initials: X
authors.lastname: Zou
authors.affiliation: Department of Endocrinology (H.F., S.L., W.L., Y.D.), Renji Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai, 200025 China; Hongqiao Institute of Medicine (H.F., Q.L., X.Z., Y.Z., J.W., Z.H.), Shanghai Tongren Hospital and Faculty of Basic Medicine, Shanghai Jiaotong University School of Medicine, Shanghai, 200025 China; Department of Pathophysiology (W.D., H.S.), Key Laboratory of Cell Differentiation and Apoptosis of Chinese Ministry of Education, Shanghai Jiaotong University School of Medicine, Shanghai, 200025 China; and Shanghai Key Laboratory for Tumor Microenvironment and Inflammation (Z.H.), Shanghai Jiaotong University School of Medicine, Shanghai, 200025 China.
authors.forename: Yihong
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Department of Endocrinology (H.F., S.L., W.L., Y.D.), Renji Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai, 200025 China; Hongqiao Institute of Medicine (H.F., Q.L., X.Z., Y.Z., J.W., Z.H.), Shanghai Tongren Hospital and Faculty of Basic Medicine, Shanghai Jiaotong University School of Medicine, Shanghai, 200025 China; Department of Pathophysiology (W.D., H.S.), Key Laboratory of Cell Differentiation and Apoptosis of Chinese Ministry of Education, Shanghai Jiaotong University School of Medicine, Shanghai, 200025 China; and Shanghai Key Laboratory for Tumor Microenvironment and Inflammation (Z.H.), Shanghai Jiaotong University School of Medicine, Shanghai, 200025 China.
authors.forename: Jiamin
authors.initials: J
authors.lastname: Wang
authors.affiliation: Department of Endocrinology (H.F., S.L., W.L., Y.D.), Renji Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai, 200025 China; Hongqiao Institute of Medicine (H.F., Q.L., X.Z., Y.Z., J.W., Z.H.), Shanghai Tongren Hospital and Faculty of Basic Medicine, Shanghai Jiaotong University School of Medicine, Shanghai, 200025 China; Department of Pathophysiology (W.D., H.S.), Key Laboratory of Cell Differentiation and Apoptosis of Chinese Ministry of Education, Shanghai Jiaotong University School of Medicine, Shanghai, 200025 China; and Shanghai Key Laboratory for Tumor Microenvironment and Inflammation (Z.H.), Shanghai Jiaotong University School of Medicine, Shanghai, 200025 China.
authors.forename: Shengxian
authors.initials: S
authors.lastname: Li
authors.affiliation: Department of Endocrinology (H.F., S.L., W.L., Y.D.), Renji Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai, 200025 China; Hongqiao Institute of Medicine (H.F., Q.L., X.Z., Y.Z., J.W., Z.H.), Shanghai Tongren Hospital and Faculty of Basic Medicine, Shanghai Jiaotong University School of Medicine, Shanghai, 200025 China; Department of Pathophysiology (W.D., H.S.), Key Laboratory of Cell Differentiation and Apoptosis of Chinese Ministry of Education, Shanghai Jiaotong University School of Medicine, Shanghai, 200025 China; and Shanghai Key Laboratory for Tumor Microenvironment and Inflammation (Z.H.), Shanghai Jiaotong University School of Medicine, Shanghai, 200025 China.
authors.forename: Wei
authors.initials: W
authors.lastname: Liu
authors.affiliation: Department of Endocrinology (H.F., S.L., W.L., Y.D.), Renji Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai, 200025 China; Hongqiao Institute of Medicine (H.F., Q.L., X.Z., Y.Z., J.W., Z.H.), Shanghai Tongren Hospital and Faculty of Basic Medicine, Shanghai Jiaotong University School of Medicine, Shanghai, 200025 China; Department of Pathophysiology (W.D., H.S.), Key Laboratory of Cell Differentiation and Apoptosis of Chinese Ministry of Education, Shanghai Jiaotong University School of Medicine, Shanghai, 200025 China; and Shanghai Key Laboratory for Tumor Microenvironment and Inflammation (Z.H.), Shanghai Jiaotong University School of Medicine, Shanghai, 200025 China.
authors.forename: Ying
authors.initials: Y
authors.lastname: Dong
authors.affiliation: Department of Endocrinology (H.F., S.L., W.L., Y.D.), Renji Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai, 200025 China; Hongqiao Institute of Medicine (H.F., Q.L., X.Z., Y.Z., J.W., Z.H.), Shanghai Tongren Hospital and Faculty of Basic Medicine, Shanghai Jiaotong University School of Medicine, Shanghai, 200025 China; Department of Pathophysiology (W.D., H.S.), Key Laboratory of Cell Differentiation and Apoptosis of Chinese Ministry of Education, Shanghai Jiaotong University School of Medicine, Shanghai, 200025 China; and Shanghai Key Laboratory for Tumor Microenvironment and Inflammation (Z.H.), Shanghai Jiaotong University School of Medicine, Shanghai, 200025 China.
authors.forename: Haipeng
authors.initials: H
authors.lastname: Sun
authors.affiliation: Department of Endocrinology (H.F., S.L., W.L., Y.D.), Renji Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai, 200025 China; Hongqiao Institute of Medicine (H.F., Q.L., X.Z., Y.Z., J.W., Z.H.), Shanghai Tongren Hospital and Faculty of Basic Medicine, Shanghai Jiaotong University School of Medicine, Shanghai, 200025 China; Department of Pathophysiology (W.D., H.S.), Key Laboratory of Cell Differentiation and Apoptosis of Chinese Ministry of Education, Shanghai Jiaotong University School of Medicine, Shanghai, 200025 China; and Shanghai Key Laboratory for Tumor Microenvironment and Inflammation (Z.H.), Shanghai Jiaotong University School of Medicine, Shanghai, 200025 China.
authors.forename: Zhaoyuan
authors.initials: Z
authors.lastname: Hou
mesh_terms: D000818:Animals; D001665:Binding Sites; D002460:Cell Line; D004268:DNA-Binding Proteins / Q000378:metabolism; D005786:Gene Expression Regulation / Q000235:genetics*; D057809:HEK293 Cells; D056945:Hep G2 Cells; D022781:Hepatocytes / Q000378:metabolism; D006801:Humans; D060588:LIM Domain Proteins / Q000235:genetics / Q000378:metabolism*; D000071518:Liver X Receptors; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D057093:Orphan Nuclear Receptors / Q000378:metabolism*; D011401:Promoter Regions, Genetic / Q000235:genetics; D011485:Protein Binding; D047491:Retinoid X Receptor gamma / Q000378:metabolism*; D015533:Transcriptional Activation / Q000235:genetics*
chemical_list: C485608:AJUBA protein, human; D004268:DNA-Binding Proteins; D060588:LIM Domain Proteins; D000071518:Liver X Receptors; C000605213:NR1H3 protein, human; C000605214:Nr1h3 protein, mouse; D057093:Orphan Nuclear Receptors; D047491:Retinoid X Receptor gamma