Functional activities of the elF2a kinase are fundamentally involved in inflammatory stress response and the development of metabolic syndrome. However, the molecular mechanism responsible for the activation of PKR upon nutrient surplus and its influences on lipid metabolism, particularly the pathogenesis of hyperlipidemia and hepatic steatosis, remain to be identified. Dr. Su will test the hypothesis that overexpression of microRNAs induced by nutrient surplus activates PKR, which subsequently mediates mitochondrial stress signaling to the endoplasmic reticulum, disturbs hepatic very low density lipoprotein (VLDL) assembly and leads to hepatic steatosis. This hypothesis will be tested using wild type and high-fat diet-fed PKR or microRNA-378/378* knockout mice models to determine the role of microRNA-378/378* in the activation of PKR induced by high-fat diet, the cross-talk between mitochondrial stress and endoplasmic reticulum stress, the regulatory effect of PKR on hepatic VLDL assembly and secretion, and their contribution to hepatic steatosis. This project links overexpression of microRNAs induced by high-fat diet with stress signaling in the development of metabolic syndrome, positioning Dr. Su for collaborations with other Project Leaders in this application. Because of her focus on hepatic steatosis and diabetes, she will target NIDDK for R01 funding. The NHLBI also is a viable alternative. Dr. Su's primary mentor. Dr. Donald Becker, is a well-known expert in redox signaling and is the Director of the COBRE-supported Redox Biology Center at UNL. Dr. Su's secondary mentor. Dr. Zempleni, has research experience in kinase signaling, endoplasmic reticulum stress, and elF2a kinases.

Public Health Relevance

Non-alcoholic fatty liver disease (NAFLD) is highly prevalent in the United States, and a protein enzyme, PKR, is a factor because its activity is increased in obesity and hepatic insulin resistance rodent models. This project stands potential to provide the first example of an enzyme being activated by small nucleotides, microRNA, in response to access nutrition supply. As such, it has strong potential to advance understanding of the pathogenesis of NAFLD and may lead to new nutrient-based strategies for NAFLD prevention and treatment.

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
Exploratory Grants (P20)
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Special Emphasis Panel (ZGM1-TWD-C (C1))
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University of Nebraska Lincoln
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Miyamoto, Yasuhiro; Mauer, Amy S; Kumar, Swarup et al. (2014) Mmu-miR-615-3p regulates lipoapoptosis by inhibiting C/EBP homologous protein. PLoS One 9:e109637
Sittiwong, Wantanee; Cordonier, Elizabeth L; Zempleni, Janos et al. (2014) ?-Keto and ?-hydroxyphosphonate analogs of biotin-5'-AMP are inhibitors of holocarboxylase synthetase. Bioorg Med Chem Lett 24:5568-71