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American Liver Foundation
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New York, New York 10006
American Association for the Study of Liver Diseases/American Liver Foundation Liver Scholar Award
University of Michigan
Project Title: Protective role of Sestrins against metabolic pathologies in liver
With the development of modern society, age- and obesity-associated liver diseases have become a major health problem of people in the United States and the world. However, the molecular mechanisms underlying metabolic pathologies in liver are not well understood. Given the current prevalence of these diseases throughout the world, a better understanding of the causes and identification of potential therapeutic strategies would have a significant impact on human health. AMP-activated protein kinase (AMPK) and target of rapamycin (TOR) are important protein kinases that have diametrically antagonistic functions in liver metabolic homeostasis. Defects in the regulatory network that modulates the AMPK-TOR balance in cells can lead to chronic activation of TOR that culminates in obesity- or age associated metabolic pathologies in liver such as hepatosteatosis and insulin resistance. Recently, Dr. Lee determined using Drosophila as a model system, that a stress-inducible protein, Sestrin functions as a negative feedback regulator of TOR. Furthermore, he established that inactivation of Drosophila Sestrin results in pronounced fat accumulation in fat body, an insect counterpart of mammalian liver. Also in mice, the loss of Sestrin2 caused aggravation of hepatosteatosis and hepatic insulin resistance upon obesity induction by high fat diet or leptin mutation. Here Dr. Lee proposes to investigate the mechanistic detail on how mouse Sestrin2 contributes to the metabolic homeostasis in liver. First, using tet-tTA tissue-specific gene modulation methods, he will examine if the metabolism-controlling role of Sestrin2 in liver is confined to hepatocytes. As Sestrin2 was previously shown to play two independent molecular roles – antioxidant and AMPK-activating functions – he will also determine which function of Sestrin2 is important for the maintenance of metabolic homeostasis in liver, using redox-inactive Sestrin2 mutant and adenovirus-mediated gene delivery method. Finally, to further clarify the molecular mechanism of Sestrin2-dependent metabolic control, Dr. Lee will modulate activities of AMPK/TOR/autophagic pathways in liver of obese Sestrin2-knockout mice through pharmacological, viral and genetic methods. Successful completion of the proposed research will provide more comprehensive understanding of the molecular network associated with obesity-associated liver pathologies and may lead to the realization of a therapeutic potential of the Sestrin protein family, ultimately enabling development of innovative treatment methods.