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Regulation of Lipid Metabolism by Dicer Revealed through SILAC Mice
Journal of Proteome Research (2012)
  • Jonathan M. Peterson, Johns Hopkins University School of Medicine
  • Tai-Chung Huang, McKusick-Nathans Institute of Genetic Medicine
  • Nandini A. Sahasrabuddhe, Manipal University
  • Min-Sik Kim, Johns Hopkins University School of Medicine
  • Derese Getnet, McKusick-Nathans Institute of Genetic Medicine
  • Yi Yang, McKusick-Nathans Institute of Genetic Medicine
  • Bidyut Ghosh, Johns Hopkins University School of Medicine
  • Raghothama Chaerkady, McKusick-Nathans Institute of Genetic Medicine
  • Steven D. Leach, McKusick-Nathans Institute of Genetic Medicine
  • Luigi Marchionni, Johns Hopkins University School of Medicine
  • G. William Wong, Johns Hopkins University School of Medicine
  • Akhilesh Pandey, Johns Hopkins University School of Medicine
Abstract
Dicer is a ribonuclease whose major role is to generate mature
microRNAs, although additional functions have been proposed. Deletion of Dicer leads to embryonic lethality in mice. To study the role of Dicer in adults, we generated mice in which administration of tamoxifen induces deletion of Dicer. Surprisingly, disruption of Dicer in adult mice induced lipid accumulation in the small intestine. To dissect the underlying mechanisms, we carried out miRNA, mRNA, and proteomic profiling of the small intestine. The proteomic analysis was done using mice metabolically labeled with heavy lysine (SILAC mice) for an in vivo readout. We identified 646 proteins, of which 80 were up-regulated >2-fold and 75 were down-regulated. Consistent with the accumulation of lipids, Dicer disruption caused a marked decrease of microsomal triglyceride transfer protein, long-chain fatty acyl-CoA ligase 5, fatty acid binding protein, and very-long-chain fatty acyl-CoA dehydrogenase, among others. We validated these results using multiple reaction monitoring (MRM) experiments by targeting proteotypic peptides. Our data reveal a previously unappreciated role of Dicer in lipid metabolism. These studies demonstrate that a systems biology approach byintegrating mouse models, metabolic labeling, gene expression profiling, and quantitative proteomics can be a powerful tool for understanding complex biological systems.
Keywords
  • dicer,
  • lipid,
  • triglyceride,
  • small intestine,
  • SILAC,
  • metabolic labeling,
  • proteomics,
  • microRNA,
  • ribosome,
  • multiple reaction monitoring
Publication Date
February 7, 2012
DOI
10.1021/pr2009884
Publisher Statement
Accepted manuscript available in PMC: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3612551/ 
Citation Information
Jonathan M. Peterson, Tai-Chung Huang, Nandini A. Sahasrabuddhe, Min-Sik Kim, et al.. "Regulation of Lipid Metabolism by Dicer Revealed through SILAC Mice" Journal of Proteome Research Vol. 11 (2012) p. 2193 - 2205 ISSN: 1535-3907
Available at: http://works.bepress.com/jonathan-peterson/9/