Regulation of Lipid Metabolism by Dicer Revealed through SILAC Mice

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 by integrating
mouse models, metabolic labeling, gene expression profiling, and quantitative
proteomics can be a powerful tool for understanding complex biological
systems.