Browsing by Author "Pan, Xiaoyan"

Now showing 1 - 3 of 3
  • Thumbnail Image
    Item
    FOXO transcription factors protect against the diet-induced fatty liver disease
    (SpringerNature, 2017-03-16) Pan, Xiaoyan; Zhang, Yang; Kim, Hyeong-Geug; Liangpunsakul, Suthat; Dong, X. Charlie; Department of Biochemistry & Molecular Biology, IU School of Medicine
    Forkhead O transcription factors (FOXOs) have been implicated in glucose and lipid homeostasis; however, the role of FOXOs in the development of nonalcoholic fatty liver disease (NAFLD) is not well understood. In this study, we designed experiments to examine the effects of two different diets-very high fat diet (HFD) and moderately high fat plus cholesterol diet (HFC)-on wildtype (WT) and liver-specific Foxo1/3/4 triple knockout mice (LTKO). Both diets induced severe hepatic steatosis in the LTKO mice as compared to WT controls. However, the HFC diet led to more severe liver injury and fibrosis compared to the HFD diet. At the molecular levels, hepatic Foxo1/3/4 deficiency triggered a significant increase in the expression of inflammatory and fibrotic genes including Emr1, Ccl2, Col1a1, Tgfb, Pdgfrb, and Timp1. Thus, our data suggest that FOXO transcription factors play a salutary role in the protection against the diet-induced fatty liver disease.
  • Thumbnail Image
    Item
    Prediction and Validation of Transcription Factors Modulating the Expression of Sestrin3 Gene Using an Integrated Computational and Experimental Approach
    (Plos, 2016-07-28) Srivastava, Rajneesh; Zhang, Yang; Xiong, Xiwen; Zhang, Xiaoning; Pan, Xiaoyan; Dong, X. Charlie; Liangpunsakul, Suthat; Janga, Sarath Chandra; Department of BioHealth Informatics, IU School of Informatics and Computing
    SESN3 has been implicated in multiple biological processes including protection against oxidative stress, regulation of glucose and lipid metabolism. However, little is known about the factors and mechanisms controlling its gene expression at the transcriptional level. We performed in silico phylogenetic footprinting analysis of 5 kb upstream regions of a diverse set of human SESN3 orthologs for the identification of high confidence conserved binding motifs (BMo). We further analyzed the predicted BMo by a motif comparison tool to identify the TFs likely to bind these discovered motifs. Predicted TFs were then integrated with experimentally known protein-protein interactions and experimentally validated to delineate the important transcriptional regulators of SESN3. Our study revealed high confidence set of BMos (integrated with DNase I hypersensitivity sites) in the upstream regulatory regions of SESN3 that could be bound by transcription factors from multiple families including FOXOs, SMADs, SOXs, TCFs and HNF4A. TF-TF network analysis established hubs of interaction that include SMAD3, TCF3, SMAD2, HDAC2, SOX2, TAL1 and TCF12 as well as the likely protein complexes formed between them. We show using ChIP-PCR as well as over-expression and knock out studies that FOXO3 and SOX2 transcriptionally regulate the expression of SESN3 gene. Our findings provide an important roadmap to further our understanding on the regulation of SESN3.
  • Thumbnail Image
    Item
    SIRT6 protects against palmitate-induced pancreatic β-cell dysfunction and apoptosis
    (BioScientifica, 2016-11) Xiong, Xiwen; Sun, Xupeng; Wang, Qingzhi; Qian, Xinlai; Zhang, Yang; Pan, Xiaoyan; Dong, X. Charlie; Biochemistry and Molecular Biology, School of Medicine
    Chronic exposure of pancreatic β-cells to abnormally elevated levels of free fatty acids can lead to β-cell dysfunction and even apoptosis, contributing to type 2 diabetes pathogenesis. In pancreatic β-cells, SIRT6 has been shown to regulate insulin secretion in response to glucose stimulation. However, what roles SIRT6 play in β-cells in response to lipotoxicity remain poorly understood. Our data indicated that SIRT6 protein and mRNA levels were reduced in islets from diabetic and aged mice. High concentrations of palmitate also led to a decrease in SIRT6 expression in MIN6 β-cells and resulted in cell dysfunction and apoptosis. Knockdown of Sirt6 caused an increase in cell apoptosis and impairment in insulin secretion in response to glucose in MIN6 cells even in the absence of high palmitate. Furthermore, overexpression of SIRT6 alleviated the palmitate-induced lipotoxicity with improved cell viability and increased glucose-stimulated insulin secretion. In summary, our data suggest that SIRT6 can protect against palmitate-induced β-cell dysfunction and apoptosis.