Person: Liew, Chong-Wee
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Liew
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Chong-Wee
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Liew, Chong-Wee
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Publication Increasing Glucose 6-Phosphate Dehydrogenase Activity Restores Redox Balance in Vascular Endothelial Cells Exposed to High Glucose(Public Library of Science, 2012) Zhang, Zhaoyun; Yang, Zhihong; Zhu, Bo; Hu, Ji; Liew, Chong-Wee; Leopold, Jane; Handy, Diane; Loscalzo, Joseph; Stanton, Robert; Zhang, Ying-YiPrevious studies have shown that high glucose increases reactive oxygen species (ROS) in endothelial cells that contributes to vascular dysfunction and atherosclerosis. Accumulation of ROS is due to dysregulated redox balance between ROS-producing systems and antioxidant systems. Previous research from our laboratory has shown that high glucose decreases the principal cellular reductant, NADPH by impairing the activity of glucose 6-phosphate dehydrogenase (G6PD). We and others also have shown that the high glucose-induced decrease in G6PD activity is mediated, at least in part, by cAMP-dependent protein kinase A (PKA). As both the major antioxidant enzymes and NADPH oxidase, a major source of ROS, use NADPH as substrate, we explored whether G6PD activity was a critical mediator of redox balance. We found that overexpression of G6PD by pAD-G6PD infection restored redox balance. Moreover inhibition of PKA decreased ROS accumulation and increased redox enzymes, while not altering the protein expression level of redox enzymes. Interestingly, high glucose stimulated an increase in NADPH oxidase (NOX) and colocalization of G6PD with NOX, which was inhibited by the PKA inhibitor. Lastly, inhibition of PKA ameliorated high glucose mediated increase in cell death and inhibition of cell growth. These studies illustrate that increasing G6PD activity restores redox balance in endothelial cells exposed to high glucose, which is a potentially important therapeutic target to protect ECs from the deleterious effects of high glucose.Publication Impaired Thermogenesis and Adipose Tissue Development in Mice with Fat-Specific Disruption of Insulin and IGF-1 Signalling(Nature Publishing Group, 2012) Boucher, Jeremie; Mori, Marcelo A.; Lee, Kevin Y.; Smyth, Graham; Liew, Chong-Wee; Macotela, Yazmin; Rourk, Michael; Bluher, Matthias; Russell, Steven; Kahn, C.Insulin and insulin-like growth factor 1 (IGF-1) play important roles in adipocyte differentiation, glucose tolerance and insulin sensitivity. Here, to assess how these pathways can compensate for each other, we created mice with a double tissue-specific knockout of insulin and IGF-1 receptors to eliminate all insulin/IGF-1 signaling in fat. These FIGIRKO mice had markedly decreased white and brown fat mass and were completely resistant to high fat diet (HFD) induced obesity and age- and HFD-induced glucose intolerance. Energy expenditure was increased in FIGIRKO mice despite a >85% reduction in brown fat mass. However, FIGIRKO mice were unable to maintain body temperature when placed at \(4^{\circ}C\). Brown fat activity was markedly decreased in FIGIRKO mice but was responsive to \(\beta3\)-receptor stimulation. Thus, insulin/IGF-1 signaling has a crucial role in the control of brown and white fat development, and, when disrupted, leads to defective thermogenesis and a paradoxical increase in basal metabolic rate.Publication \(\Delta\)40 Isoform of p53 Controls \(\beta\)-Cell Proliferation and Glucose Homeostasis in Mice(American Diabetes Association, 2011) Hinault, Charlotte; Kawamori, Dan; Liew, Chong-Wee; Maier, Bernhard; Hu, Jiang; Keller, Susanna R.; Mirmira, Raghavendra G.; Scrable, Heidi; Kulkarni, RohitObjective: Investigating the dynamics of pancreatic \(\beta\)-cell mass is critical for developing strategies to treat both type 1 and type 2 diabetes. p53, a key regulator of the cell cycle and apoptosis, has mostly been a focus of investigation as a tumor suppressor. Although p53 alternative transcripts can modulate p53 activity, their functions are not fully understood. We hypothesized that \(\beta\)-cell proliferation and glucose homeostasis were controlled by \(\Delta\)40p53, a p53 isoform lacking the transactivation domain of the full-length protein that modulates total p53 activity and regulates organ size and life span in mice. Research Design and Methods: We phenotyped metabolic parameters in \(\Delta\)40p53 transgenic (p44tg) mice and used quantitative RT-PCR, Western blotting, and immunohistochemistry to examine \(\beta\)-cell proliferation. Results: Transgenic mice with an ectopic p53 gene encoding \(\Delta\)40p53 developed hypoinsulinemia and glucose intolerance by 3 months of age, which worsened in older mice and led to overt diabetes and premature death from \(\sim\)14 months of age. Consistent with a dramatic decrease in \(\beta\)-cell mass and reduced \(\beta\)-cell proliferation, lower expression of cyclin D2 and pancreatic duodenal homeobox-1, two key regulators of proliferation, was observed, whereas expression of the cell cycle inhibitor p21, a p53 target gene, was increased. Conclusions: These data indicate a significant and novel role for \(\Delta\)40p53 in \(\beta\)-cell proliferation with implications for the development of age-dependent diabetes.Publication Insulin Signaling Regulates Mitochondrial Function in Pancreatic β-Cells(Public Library of Science, 2009) Liu, Siming; Okada, Terumasa; Assmann, Anke; Soto, Jamie; Liew, Chong-Wee; Bugger, Heiko; Shirihai, Orian S.; Abel, E. Dale; Kulkarni, RohitInsulin/IGF-I signaling regulates the metabolism of most mammalian tissues including pancreatic islets. To dissect the mechanisms linking insulin signaling with mitochondrial function, we first identified a mitochondria-tethering complex in β-cells that included glucokinase (GK), and the pro-apoptotic protein, BADS. Mitochondria isolated from β-cells derived from β-cell specific insulin receptor knockout (βIRKO) mice exhibited reduced BADS, GK and protein kinase A in the complex, and attenuated function. Similar alterations were evident in islets from patients with type 2 diabetes. Decreased mitochondrial GK activity in βIRKOs could be explained, in part, by reduced expression and altered phosphorylation of BADS. The elevated phosphorylation of p70S6K and JNK1 was likely due to compensatory increase in IGF-1 receptor expression. Re-expression of insulin receptors in βIRKO cells partially restored the stoichiometry of the complex and mitochondrial function. These data indicate that insulin signaling regulates mitochondrial function and have implications for β-cell dysfunction in type 2 diabetes.