DEC 17, 2019 9:00 AM PST

The role of SIRT1/LXR signaling in diabetic retinopathy

Speaker
  • Research Fellow, Michigan State University
    Biography
      My name is Sandra Hammer. I am a postdoctoral fellow in the Busik Laboratory at Michigan State University. Prior to being at MSU, I attended Vanderbilt University where I obtained my PhD in Cell and Developmental Biology under the mentorship of John Penn. Prior to this, I got my BS degree from the University of Miami.
      Scientifically, I am interested in the role that cholesterol metabolism and inflammation play in progression of microvascular disease. I am specifically interested in diabetes-induced retinal diseases. I am currently working on elucidating the role that the SIRT1/LXR signaling pathway plays in retinopahty progression. I have discovered the novel involvement of this pathway in preventing disease progression and am very interested in strategies that increase SIRT1/LXR signaling. My long term goals are to develop a energetic and productive independent research program well suited to investigate lipid dysregulation in microvascular complications.

    Abstract
    DATE:  December 17, 2019
    TIME:   9:00am PST, 12:00pm EST
     
    Purpose:
    Liver x receptors (LXRs) are hypothesized to serve as a link between lipid metabolism and inflammation by promoting cholesterol efflux as well as exhibiting anti-inflammatory properties. NAD-dependent deacetylase SIRT1 is known to promote insulin secretion, reduce glucose tolerance and to play a critical role in regulating inflammation. SIRT1 has also been shown to interact with LXR to promote LXR activation. Additionally, previous literature has shown that starvation increases SIRT1 levels in mice. The purpose of this study was to investigate the role of SIRT1-LXR activation in control of inflammation and subsequent metabolic changes in retinal endothelial cells.
     
    Methods:
    Bovine retinal endothelial cells (BRECs) were treated with diabetic relevant stimulus TNFα (10ng/ml); LXR activator, DMHCA (1uM); or SIRT1 activator, SRT1720 (1uM). In order to model calorie restriction in vitro BRECs were serum starved (0% FBS) for 24hrs. SIRT1, IL1β, ABCA1 and ABCG1 were analyzed by qRT-PCR. Sirt1 activity was measured via histone deacetylase activity (HDAC) assay. LXR acetylation was measured via western blot analysis. Results: Treatment with pro-inflammatory cytokine, TNFα (10ng/ml) for 24hrs significantly increased cholesterol levels (p=0.0233, n=6), IL1β expression, IL6 expression and resulted in decreased levels of HDAC activity in BRECs. Activation of LXR or SIRT1 prevented TNFα-induced inflammation. Serum starvation resulted in a significant increase in HDAC activity (p=0.0005, n=6) and SIRT1 expression levels. Lastly, serum starvation caused a decrease in LXR acetylated levels in BRECs.
     
    Conclusion:
    The results of this study demonstrate that serum starvation promotes activation of the SIRT1-LXR pathway metabolism in retinal endothelial cells. Therefore, this study suggests that therapeutic fasting may serve to activate the SIRT1-LXR pathway providing the dual benefits of decreasing inflammation and promoting cholesterol metabolism in the retina.
     
    Learning Objectives:
    • Understand the role of SIRT1-LXR activation in control of inflammation and subsequent metabolic changes in retinal endothelial cells.
    • Demonstrate how serum starvation promotes activation of the SIRT1-LXR pathway metabolism in retinal endothelial cells.
    • Explain how therapeutic fasting may serve to activate the SIRT1-LXR pathway providing the dual benefits of decreasing inflammation and promoting cholesterol metabolism in the retina.
     
     
     
     
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